Alpha-substituted carboxylic acid derivatives

ABSTRACT

The α-substituted carboxylic acid derivatives having the formula (I):  
                 
 
     wherein R 1  is an alkyl group, etc., R 2  is a hydrogen atom, etc., R 3  is a hydrogen atom, etc., A is ═CH-group, etc., B is an oxygen atom, etc., W 1  is a C 1 -C 8  alkylene group, W 2  is a single bond or a C 1 -C 8  alkylene group, X is a hydrogen atom, etc., Y is an oxygen atom, etc., and Z 1  is an alkoxy group, etc., and pharmacologically acceptable salts, esters and amides thereof are useful for treatment and/or prevention of diabetes mellitus, impaired glucose tolerance, gestational diabetes mellitus, or the like. Some of the derivatives of the formula (I) are novel compounds.

[0001] This application is a continuation-in-part application ofInternational Application PCT/JP00/02215 filed Apr. 6, 2000 (notpublished in English) which is incorporated herein by this reference.

TECHNICAL FIELD

[0002] The present invention relates to α-substituted carboxylic acidderivatives having excellent insulin resistance improving activity,hypoglycemic activity, anti-inflammatory activity, immunoregulatoryactivity, aldose reductase inhibiting activity, 5-lipoxygenaseinhibiting activity, peroxidized lipid production suppressing activity,PPAR activating activity, anti-osteoporosis activity, leukotrienesantagonistic activity, adipose cell formation promoting activity, cancercell proliferation suppressing activity or calcium antagonisticactivity, to their pharmacologically acceptable esters, to theirpharmacologically acceptable amides and to their pharmacologicallyacceptable salts.

[0003] Further, the present invention is directed to preventives and/ortherapeutic agents for diseases such as diabetes mellitus, hyperlipemia,obesity, glucose tolerance insufficiency, hypertension, fatty liver,diabetic complications (e.g. retinopathy, nephropathy, neurosis,cataract, coronary artery diseases, etc.), arteriosclerosis, gestationaldiabetes mellitus, polycystic ovary syndrome, cardiovascular diseases(e.g. ischemic heart disease, etc.), cell injury lesion (e.g. cerebralinjury induced by stroke, etc.) caused by atherosclerosis or ischemicheart disease, gout, inflammatory diseases (e.g. arthrosteitis, pain,fervescence, rheumatic arthritis, inflammatory enteritis, acne, sunburn,psoriasis, eczema, allergic diseases, asthma, GI ulcer, cachexia,autoimmune disease, pancreatitis, etc.), cancer, osteoporosis, cataract,and so on containing said α-substituted carboxylic acid derivatives,their pharmacologically acceptable esters, their pharmacologicallyacceptable amides or their pharmacologically acceptable salts as anactive ingredient.

[0004] Furthermore, this invention concerns a pharmaceutical composition(particularly, preventives and/or therapeutic agents for diabetesmellitus or diabetic complications) containing at least one ofsulfonylureas, α-glucosidase inhibitors, aldose reductase inhibitors,biguanides, statin type compounds, squalene synthesis inhibitors,fibrate type compounds, LDL disassimilation promoters, angiotensin IIantagonists, angiotensin converting enzyme inhibitors, anti-canceragents, and RXR activators (RXR agonists) together with saidα-substituted carboxylic acid derivatives, their pharmacologicallyacceptable esters, their pharmacologically acceptable amides or theirpharmacologically acceptable salts.

[0005] 1. Background Technology

[0006] Some of the α-substituted carboxylic acid derivatives of thepresent application are disclosed in (1) JP Unexamined Pub. H8(1996)-504194 Gazette, (2) JP Unexamined Pub. H10 (1998)-501222 Gazette,(3) JP Unexamined Pub. H10 (1998)-504808 Gazette, (4) JP Unexamined Pub.H10 (1998)-114751 Gazette, (5) WO 98/31359 Gazette. However, theactivities of the compounds described in these Gazettes are astherapeutic agents for anti-platelet aggregation, osteoclast mediatingbone resorption suppression, osteoporosis and the like, which aredifferent from those of the present invention.

[0007] Further, compounds showing an effect in treating diabetesmellitus or hypoglycemic activity are disclosed in (6) WO 97/31907Gazette. However, the compounds described in said Gazette may have abenzimidazole ring, one of the structural features of the compounds inthe present application also have the same group, but on the benzenering of said benzimidazole ring in said Gazette there is no substituentor, if any substituent is present there, said substituent is only alower alkyl group. On the other hand, the compounds of the presentinvention have comparatively bulky substituent(s) on the benzene ring ofthe benzimidazole ring, so they are different from the compounds of saidGazette.

[0008] Moreover, compounds having an effect in treating diabetesmellitus are disclosed in (7) WO 99/29640 Gazette. However, thecompounds described in said Gazette may be α-carboxylic acids having abenzimidazole structure similar to the compounds of the presentapplication, but they are different from the compounds of the presentapplication, because in this case the α-substituent is an amino group ora protecting group thereof such as an alkoxycarbonyl group or analkoxycarbonyl group which is comparatively easily removable. Inaddition, the compounds described in said Gazette are different fromthose of the present application in the nature of their fibroblastproliferation factor antagonism effects.

[0009] 2. Disclosure of the Invention

[0010] As the result of investigations for a long time on the search ofsynthesis and pharmacology of a series of said α-substituted carboxylicacid derivatives, their pharmacologically acceptable esters, theirpharmacologically acceptable amides and their pharmacologicallyacceptable salts, the present inventors have found the features thatsaid α-substituted carboxylic acid derivatives have excellent insulinresistance improving activity, hypoglycemic activity, anti-inflammatoryactivity, immunoregulatory activity, aldose reductase inhibitingactivity, 5-lipoxygenase inhibiting activity, peroxidized lipidproduction suppressing activity, PPAR activating activity,anti-osteoporosis activity, leukotrienes antagonistic activity, adiposecell formation promoting activity, cancer cell proliferation suppressingactivity or calcium antagonistic activity, with less side effects andhigh lipophilic solubility. Thus, the present invention has beenestablished.

[0011] The other object of the present invention is to providepreventives and/or therapeutic agents against diseases such as diabetesmellitus, hyperlipemia, obesity, glucose tolerance insufficiency,hypertension, fatty liver, diabetic complications (e.g. retinopathy,nephropathy, neurosis, cataract, coronary artery diseases, etc.),arteriosclerosis, gestational diabetes mellitus, polycystic ovarysyndrome, cardiovascular diseases (e.g. ischemic heart disease, etc.),cell injury lesion (e.g. cerebral injury induced by stroke, etc.) causedby aterosclerosis or ischemic heart disease, gout, inflammatory diseases(e.g. arthrosteitis, pain, fervescence, rheumatic arthritis,inflammatory enteritis, acne, sunburn, psoriasis, eczema, allergicdiseases, asthma, GI ulcer, cachexia, autoimmune disease, pancreatitis,etc.), cancer, osteoporosis, cataract, and so on containing saidα-substituted carboxylic acid derivatives, their pharmacologicallyacceptable esters, their pharmacologically acceptable amides or theirpharmacologically acceptable salts as an active ingredient. Further,another object of the present invention is to provide a pharmaceuticalcomposition (particularly, preventives and/or therapeutic agents fordiabetes mellitus or diabetic complications) containing at least one ofsulfonylureas, α-glucosidase inhibitors, aldose reductase inhibitors,biguanides, statins type compounds, squalene synthesis inhibitors,fibrate type compounds, LDL disassimilation promotors, angiotensin IIantagonists, angiotensin converting enzyme inhibitors, anti-canceragents, and RXR activators (RXR agonists) together with saidα-substituted carboxylic acid derivatives, their pharmacologicallyacceptable esters, their pharmacologically acceptable amides or theirpharmacologically acceptable salts. The present invention relates toα-substituted carboxylic acid derivatives having the general formula(I):

[0012] [wherein

[0013] R₁, R₂ and R₃ are the same or different, and each is a (i)hydrogen atom, (ii) C₁-C₆ alkyl group, (iii) C₆-C₁₀ aryl group(optionally having 1-5 substituting moieties α₁ hereafter described),(iv) C₇-C₁₆ aralkyl group (optionally having 1-5 substituting moietiesα₁ hereafter described on the aryl moiety thereof), (v) C₁-C₆alkylsulfonyl group, (vi) C₁-C₆ halogenoalkylsulfonyl group, (vii)C₆-C₁₀ arylsulfonyl group (optionally having 1-5 substituting moietiesα₁ hereafter described) or (viii) C₇-C₁₆ aralkylsulfonyl group(optionally having 1-5 substituting moieties α₁ hereafter described onthe aryl moiety thereof),

[0014] A is a nitrogen atom or ═CH-group,

[0015] B is an oxygen atom or a sulfur atom,

[0016] W₁ is a C₁-C₈ alkylene group,

[0017] W₂ is a single bond or a C₁-C₈ alkylene group,

[0018] X is a (i) hydrogen atom, (ii) C₁-C₆ alkyl group, (iii) C₁-C₆halogenoalkyl group, (iv) C₁-C₆ alkoxy group, (v) halogen atom, (vi)hydroxy group, (vii) cyano group, (viii) nitro group, (ix) C₃-C₁₀cycloalkyl group, (x) C₆-C₁₀ aryl group (optionally having 1-5substituting moieties β hereafter described), (xi) C₇-C₁₆ aralkyl group(optionally having 1-5 substituting moieties β hereafter described onthe aryl moiety thereof), (xii) C₁-C₇ aliphatic acyl group, (xiii)C₄-C₁₁ cycloalkylcarbonyl group, (xiv) C₇-C₁₁ arylcarbonyl group(optionally having 1-5 substituting moieties β hereafter described),(xv) C₈-C₁₇ aralkylcarbonyl group (optionally having 1-5 substitutingmoieties β hereafter described on the aryl moiety thereof), (xvi)monocyclic type heteroaromatic ring-carbonyl group (optionally having1-5 substituting moieties β hereafter described), (xvii) carbamoylgroup, (xviii) C₇-C₁₁ arylaminocarbonyl group (optionally having 1-5substituting moieties β hereafter described on the aryl moiety thereof)or (xix) amino group (optionally having 1 to 2 substituting moieties βdescribed hereafter),

[0019] Y is an oxygen atom or S(O)p (wherein p is an integer from 0 to2),

[0020] Z₁ is a (i) hydrogen atom, (ii) C₁-C₆ alkyl group, (iii) C₁-C₆alkoxy group, (iv) C₁-C₆ alkylthio group, (v) halogen atom, (vi) C₆-C₁₀aryl group (optionally having 1-5 substituting moieties α₁ hereafterdescribed), (vii) C₇-C₁₆ aralkyl group (optionally having 1-5substituting moieties α₁ hereafter described on the aryl moietythereof), (viii) C₆-C₁₀ aryloxy group (optionally having 1-5substituting moieties α₁ hereafter described), (ix) C₇-C₁₆ aralkyloxygroup (optionally having 1-5 substituting moieties α₁ hereafterdescribed on the aryl moiety thereof), (x) C₃-C₁₀ cycloalkyloxy group,(xi) C₃-C₁₀ cycloalkylthio group, (xii) saturated heterocyclic ring-oxygroup (optionally having 1-5 substituting moieties α₁ hereafterdescribed), (xiii) monocyclic type heteroaromatic ring-oxy group(optionally having 1-5 substituting moieties α₁ hereafter described),(xiv) C₆-C₁₀ arylthio group (optionally having 1-5 substituting moietiesα₁ hereafter described on the aryl moiety thereof), (xv) C₇-C₁₆aralkylthio group (optionally having 1-5 substituting moieties α₁hereafter described on the aryl moiety thereof), (xvi) saturatedheterocyclic ring-thio group (optionally having 1-5 substitutingmoieties α₁ hereafter described), (xvii) monocyclic type heteroaromaticring-thio group (optionally having 1-5 substituting moieties α₁hereafter described), (xviii) amino group (optionally having 1-2substituting moieties α₁ hereafter described) or (xix) hydroxy group,

[0021] said substituting moiety α₁ is a (i) C₁-C₆ alkyl group, (ii)C₁-C₆ halogenoalkyl group, (iii) C₁-C₆ alkoxy group, (iv) halogen atom,(v) hydroxy group, (vi) cyano group, (vii) nitro group, (viii) C₃-C₁₀cycloalkyl group, (ix) C₆-C₁₀ aryl group (optionally having 1-5substituting moieties β hereafter described), (x) C₇-C₁₆ aralkyl group(optionally having 1-5 substituting moieties β hereafter described onthe aryl moiety thereof), (xi) C₁-C₇ aliphatic acyl group, (xii) C₄-C₁₁cycloalkylcarbonyl group, (xiii) C₇-C₁₁ arylcarbonyl group (optionallyhaving 1-5 substituting moieties β hereafter described), (xiv) C₈-C₁₇aralkylcarbonyl group (optionally having 1-5 substituting moieties βhereafter described on the aryl moiety thereof), (xv) monocyclic typeheteroaromatic ring-carbonyl group (optionally having 1-5 substitutingmoieties β hereafter described), (xvi) carbamoyl group, (xvii) C₇-C₁₁arylaminocarbonyl group (optionally having 1-5 substituting moieties βhereafter described on the aryl moiety thereof), (xviii) amino group(optionally having 1 to 2 substituting moieties β described hereafter)or (xix) carboxyl group,

[0022] said substituting moiety β is a (i) C₁-C₁₀ to alkyl group, (ii)halogen atom, (iii) C₆-C₁₀ aryl group (optionally having 1-5substituting moieties γ hereafter described), (iv) C₇-C₁₆ aralkyl group(optionally having 1-5 substituting moieties γ hereafter described onthe aryl moiety thereof), (v) C₁-C₇ aliphatic acyl group, (vi) C₇-C₁₁arylcarbonyl group (optionally having 1-5 substituting moieties γhereafter described), (vii) C₈-C₁₇ aralkylcarbonyl group (optionallyhaving 1-5 substituting moieties γ hereafter described on the arylmoiety thereof), (viii) C₄-C₁₁ cycloalkylcarbonyl group, (ix) monocyclictype heteroaromatic ring-carbonyl group (optionally having 1-5substituting moieties γ hereafter described), (x) carbamoyl group or(xi) C₇-C₁₁ arylaminocarbonyl group (optionally having 1-5 substitutingmoieties γ hereafter described on the aryl moiety thereof), and

[0023] said substituting moiety γ is a C₁-C₆ alkyl group, C₁-C₆halogenoalkyl group, halogen atom or hydroxy group],

[0024] the general formula (II)

[0025] [wherein

[0026] R₁, R₂ and R₃ are the same or different, and each is a (i)hydrogen atom, (ii) C₁-C₆ alkyl group, (iii) C₆-C₁₀ aryl group(optionally having 1-5 substituting moieties α₁ hereafter described),(iv) C₇-C₁₆ aralkyl group (optionally having 1-5 substituting moietiesα₁ hereafter described on the aryl moiety thereof), (v) C₁-C₆alkylsulfonyl group, (vi) C₁-C₆ halogenoalkylsulfonyl group, (vii)C₆-C₁₀ arylsulfonyl group (optionally having 1-5 substituting moietiesα₁ hereafter described) or (viii) C₇-C₁₆ aralkylsulfonyl group(optionally having 1-5 substituting moieties α₁ hereafter described onthe aryl moiety thereof),

[0027] A is a nitrogen atom or ═CH-group,

[0028] B is an oxygen atom or a sulfur atom,

[0029] W₁ is a C₁-C₈ alkylene group,

[0030] W₂ is a single bond or a C₁-C₈ alkylene group,

[0031] X is a (i) hydrogen atom, (ii) C₁-C₆ alkylene group, (iii) C₁-C₆halogenoalkyl group, (iv) C₁-C₆ alkoxy group, (v) halogen atom, (vi)hydroxy group, (vii) cyano group, (viii) nitro group, (ix) C₃-C₁₀cycloalkyl group, (x) C₆-C₁₀ aryl group (optionally having 1-5substituting moieties β hereafter described), (xi) C₇-C₁₆ aralkyl group(optionally having 1-5 substituting moieties β hereafter described onthe aryl moiety thereof), (xii) C₁-C₇ aliphatic acyl group, (xiii)C₄-C₁₁ cycloalkylcarbonyl group, (xiv) C₇-C₁₁ arylcarbonyl group(optionally having 1-5 substituting moieties β hereafter described),(xv) C₈-C₁₇ aralkylcarbonyl group (optionally having 1-5 substitutingmoieties β hereafter described on the aryl moiety thereof), (xvi)monocyclic type heteroaromatic ring-carbonyl group (optionally having1-5 substituting moieties β described hereafter), (xvii) carbamoylgroup, (xviii) C₇-C₁₁ arylaminocarbonyl group (optionally having 1-5substituting moieties β hereafter described on the aryl moiety thereof)or (xix) amino group (optionally having 1 to 2 substituting moieties βdescribed hereafter),

[0032] Y is an oxygen atom or S(O)p group (wherein p is an integer from0 to 2)

[0033] Z₂ is a saturated heterocyclic ring (optionally having 1-5substituting moieties α₁ hereafter described), or C₆-C₁₀ aryl group(optionally having 1-5 substituting moieties α₂ hereafter described),

[0034] said substituting moiety α₁ is a (i) C₁-C₆ alkyl group, (ii)C₁-C₆ halogenoalkyl group, (iii) C₁-C₆ alkoxy group, (iv) halogen atom,(v) hydroxy group, (vi) cyano group, (vii) nitro group, (viii) C₃-C₁₀cycloalkyl group, (ix) C₆-C₁₀ aryl group (optionally having 1-5substituting moieties β hereafter described), (x) C₇-C₁₆ aralkyl group(optionally having 1-5 substituting moieties β hereafter described onthe aryl moiety thereof), (xi) C₁-C₇ aliphatic-acyl group, (xii) C₄-C₁₁cycloalkylcarbonyl group, (xiii) C₇-C₁₁ arylcarbonyl group (optionallyhaving 1-5 substituting moieties β hereafter described), (xiv) C₈-C₁₇aralkylcarbonyl group (optionally having 1-5 substituting moieties βhereafter described on the aryl moiety thereof), (xv) monocyclic typeheteroaromatic ring-carbonyl group (optionally having 1-5 substitutingmoieties β hereafter described), (xvi) carbamoyl group, (xvii) C₇-C₁₁arylaminocarbonyl group (optionally having 1-5 substituting moieties βhereafter described on the aryl moiety thereof), (xviii) amino group(optionally having 1 to 2 substituting moieties β described hereafter)or (xix) carboxyl group,

[0035] said substituting moiety α₂ is a (i) C₃-C₁₀ cycloalkyl group,(ii) C₆-C₁₀ aryl group (optionally having 1-5 substituting moieties βhereafter described), (iii) C₇-C₁₆ aralkyl group (optionally having 1-5substituting moieties β hereafter described on the aryl moiety thereof),(iv) C₁-C₇ aliphatic acyl group, (v) C₄-C₁₁ cycloalkylcarbonyl group,(vi) C₇-C₁₁ arylcarbonyl group (optionally having 1-5 substitutingmoieties β hereafter described), (vii) C₈-C₁₇ aralkylcarbonyl group(optionally having 1-5 substituting moieties β hereafter described onthe aryl moiety thereof), (viii) monocyclic type heteroaromaticring-carbonyl group (optionally having 1-5 substituting moieties βhereafter described), or (ix) C₇-C₁₁ arylaminocarbonyl group (optionallyhaving 1-5 substituting moieties β hereafter described on the arylmoiety thereof),

[0036] said substituting moiety β is a (i) C₁-C₁₀ alkyl group, (ii)halogen atom, (iii) C₆-C₁₀ aryl group (optionally having 1-5substituting moieties γ hereafter described), (iv) C₇-C₁₆ aralkyl group(optionally having 1-5 substituting moieties γ hereafter described onthe aryl moiety thereof), (v) C₁-C₇ aliphatic acyl group, (vi) C₇-C₁₁arylcarbonyl group (optionally having 1-5 substituting moieties γhereafter described), (vii) C₈-C₁₇ aralkylcarbonyl group (optionallyhaving 1-5 substituting moieties γ hereafter described on the arylmoiety thereof), (viii) C₄-C₁₁ cycloalkylcarbonyl group, (ix) monocyclictype heteroaromatic ring-carbonyl group (optionally having 1-5substituting moieties γ hereafter described), (x) carbamoyl group or(xi) C₇-C₁₁ arylaminocarbonyl group (optionally having 1-5 substitutingmoieties γ hereafter described on the aryl moiety thereof), and

[0037] said substituting moiety γ is a C₁-C₆ alkyl group, C₁-C₆halogenoalkyl group, halogen group or hydroxy group],

[0038] the general formula (III)

[0039] [wherein

[0040] R₁, R₂ and R₃ are the same or different, and each is a (i)hydrogen atom, (ii) C₁-C₆ alkyl group, (iii) C₆-C₁₀ aryl group(optionally having 1-5 substituting moieties α₁ hereafter described),(iv) C₇-C₁₆ aralkyl group (optionally having 1-5 substituting moietiesα₁ hereafter described on the aryl moiety thereof), (v) C₁-C₆alkylsulfonyl group, (vi) C₁-C₆ halogenoalkylsulfonyl group, (vii)C₆-C₁₀ arylsulfonyl group (optionally having 1-5 substituting moietiesα₁ hereafter described) or (viii) C₇-C₁₆ aralkylsulfonyl group(optionally having 1-5 substituting moieties α₁ hereafter described onthe aryl moiety thereof),

[0041] A is a nitrogen atom or ═CH-group,

[0042] B is an oxygen atom or a sulfur atom,

[0043] W₁ is a C₁-C₈ alkylene group,

[0044] W₂ is a single bond or a C₁-C₈ alkylene group,

[0045] X is a (i) hydrogen atom, (ii) C₁-C₆ alkyl group, (iii) C₁-C₆halogenoalkyl group, (iv) C₁-C₆ alkoxy group, (v) halogen atom, (vi)hydroxy group, (vii) cyano group, (viii) nitro group, (ix) C₃-C₁₀cycloalkyl group, (x) C₆-C₁₀ aryl group (optionally having 1-5substituting moieties β hereafter described), (xi) C₇-C₁₆ aralkyl group(optionally having 1-5 substituting moieties β hereafter described onthe aryl moiety thereof), (xii) C₁-C₇ aliphatic acyl group, (xiii)C₄-C₁₁ cycloalkylcarbonyl group, (xiv) C₇-C₁₁ arylcarbonyl group(optionally having 1-5 substituting moieties β hereafter described),(xv) C₈-C₁₇ aralkylcarbonyl group (optionally having 1-5 substitutingmoieties β hereafter described on the aryl moiety thereof), (xvi)monocyclic type heteroaromatic ring-carbonyl group (optionally having1-5 substituting moieties β hereafter described), (xvii) carbamoylgroup, (xviii) C₇-C₁₁ arylaminocarbonyl group (optionally having 1-5substituting moieties β hereafter described on the aryl moiety thereof)or (xix) amino group (optionally having 1 to 2 substituting moieties βdescribed hereafter),

[0046] Y is an oxygen atom or S(O)p group (wherein p is an integer from0 to 2),

[0047] Z₃ is a (i) C₁-C₆ alkyl group, (ii) C₆-C₁₀ aryl group (optionallycontaining 1-5 substituting moieties α₁ hereafter described), (iii)C₇-C₁₆ aralkyl group (optionally containing 1-5 substituting moieties α₁hereafter described on the aryl moiety threof), (iv) C₃-C₁₀ cycloalkylgroup or (v) saturated heterocyclic ring group (optionally containing1-5 substituting moieties α₁ hereafter described),

[0048] said substituting moiety α₁ is a (i) C₁-C₆ alkyl group, (ii)C₁-C₆ halogenoalkyl group, (iii) C₁-C₆ alkoxy group, (iv) halogen atom,(v) hydroxy group, (vi) cyano group, (vii) nitro group, (viii) C₃-C₁₀cycloalkyl group, (ix) C₆-C₁₀ aryl group (optionally having 1-5substituting moieties β hereafter described), (x) C₇-C₁₆ aralkyl group(optionally having 1-5 substituting moieties β hereafter described onthe aryl moiety thereof), (xi) C₁-C₇ aliphatic acyl group, (xii) C₄-C₁₁cycloalkylcarbonyl group, (xiii) C₇-C₁₁ arylcarbonyl group (optionallyhaving 1-5 substituting moieties β hereafter described), (xiv) C₈-C₁₇aralkylcarbonyl group (optionally having 1-5 substituting moieties βhereafter described on the aryl moiety thereof), (xv) monocyclic typeheteroaromatic ring-carbonyl group (optionally having 1-5 substitutingmoieties β hereafter described), (xvi) carbamoyl group, (xvii) C₇-C₁₁arylaminocarbonyl group (optionally having 1-5 substituting moieties βhereafter described on the aryl moiety thereof), (xviii) amino group(optionally having 1 to 2 substituting moieties β described hereafter)or (xix) carboxyl group,

[0049] said substituting moiety β is a (i) C₁-C₁₀ alkyl group, (ii)halogen atom, (iii) C₆-C₁₀ aryl group (optionally having 1-5substituting moieties γ hereafter described), (iv) C₇-C₁₆ aralkyl group(optionally having 1-5 substituting moieties γ hereafter described onthe aryl moiety thereof), (v) C₁-C₇ aliphatic acyl group, (vi) C₇-C₁₁arylcarbonyl group (optionally having 1-5 substituting moieties γhereafter described), (vii) C₈-C₁₇ aralkylcarbonyl group (optionallyhaving 1-5 substituting moieties γ hereafter de scribed on the arylmoiety thereof), (viii) C₄-C₁₁ cycloalkylcarbonyl group, (ix) monocyclictype heteroaromatic ring-carbonyl group (optionally having 1-5substituting moieties γ hereafter described), (x) carbamoyl group or(xi) C₇-C₁₁ arylaminocarbonyl group (optionally having 1-5 substitutingmoieties γ hereafter described on the aryl moiety thereof), and

[0050] said substituting moiety γ is a C₁-C₆ alkyl group, C₁-C₆halogenoalkyl group, halogen atom or hydroxy group], or

[0051] the general formula (IV)

[0052] [wherein

[0053] R₁, R₂ and R₃ are the same or different, and each is a (i)hydrogen atom, (ii) C₁-C₆ alkyl group, (iii) C₆-C₁₀ aryl group(optionally having 1-5 substituting moieties α₁ hereafter described),(iv) C₇-C₁₆ aralkyl group (optionally having 1-5 substituting moietiesα₁ hereafter described on the aryl moiety thereof), (v) C₁-C₆alkylsulfonyl group, (vi) C₁-C₆ halogenoalkylsulfonyl group, (vii)C₆-C₁₀ arylsulfonyl group (optionally having 1-5 substituting moietiesα₁ hereafter described) or (viii) C₇-C₁₆ aralkylsulfonyl group(optionally having 1-5 substituting moieties α₁ hereafter described onthe aryl moiety thereof),

[0054] R₄ is a (i) C₁-C₆ alkyl group, (ii) C₆-C₁₀ aryl group (optionallyhaving 1-5 substituting moieties α₁ hereafter described) or (iii) C₇-C₁₆aralkyl group (optionally having 1-5 substituting moieties α₁ hereafterdescribed on the aryl moiety thereof),

[0055] A is a nitrogen atom or ═CH-group,

[0056] B is an oxygen atom or a sulfur atom,

[0057] W₁ is a C₁-C₈ alkylene group,

[0058] W₂ is a single bond or a C₁-C₈ alkylene group,

[0059] X is a (i) hydrogen atom, (ii) C₁-C₆ alkyl group, (iii) C₁-C₆halogenoalkyl group, (iv) C₁-C₆ alkoxy group, (v) halogen atom, (vi)hydroxy group, (vii) cyano group, (viii) nitro group, (ix) C₃-C₁₀cycloalkyl group, (x) C₆-C₁₀ aryl group (optionally having 1-5substituting moieties β hereafter described), (xi) C₇-C₁₆ aralkyl group(optionally having 1-5 substituting moieties, hereafter described on thearyl moiety thereof), (xii) C₁-C₇ aliphatic acyl group, (xiii) C₄-C₁₁cycloalkylcarbonyl group, (xiv) C₇-C₁₁ arylcarbonyl group (optionallyhaving 1-5 substituting moieties β hereafter described), (xv) C₈-C₁₇aralkylcarbonyl group (optionally having 1-5 substituting moieties βhereafter described on the aryl moiety thereof), (xvi) monocyclic typeheteroaromatic ring-carbonyl group (optionally having 1-5 substitutingmoieties β hereafter described), (xvii) carbamoyl group, (xviii) C₇-C₁₁arylaminocarbonyl group (optionally having 1-5 substituting moieties βhereafter described on the aryl moiety thereof) or (xix) amino group(optionally having 1 to 2 substituting moieties β described hereafter),

[0060] Y is an oxygen atom or S(O)p (wherein p is an integer from 0 to2),

[0061] Z₄ is a (i) C₁-C₆ alkoxy group, (ii) C₁-C₆ alkylthio group, (iii)halogen atom, (iv) C₆-C₁₀ aryl group (optionally having 1-5 substitutingmoieties α₁ hereafter described), (v) C₇-C₁₆ aralkyl group (optionallyhaving 1-5 substituting moieties α₁ hereafter described on the arylmoiety thereof), (vi) C₆-C₁₀ aryloxy group (optionally having 1-5substituting moieties α₁ hereafter described), (vii) C₇-C₁₆ aralkyloxygroup (optionally having 1-5 substituting moieties α₁ hereafterdescribed on the aryl moiety thereof), (viii) C₃-C₁₀ cycloalkyloxygroup, (ix) C₃-C₁₀ cycloalkylthio group, (x) saturated heterocyclicring-oxy group (optionally having 1-5 substituting moieties α₁ hereafterdescribed), (xi) monocyclic type heteroaromatic ring-oxy group(optionally having 1-5 substituting moieties α₁ hereafter described),(xii) C₆-C₁₀ arylthio group (optionally having 1-5 substituting moietiesα₁ hereafter described), (xiii) C₇-C₁₆ aralkylthio group (optionallyhaving 1-5 substituting moieties α₁ hereafter described on the arylmoiety thereof), (xiv) saturated heterocyclic ring-thio group(optionally having 1-5 substituting moieties α₁ hereafter described),(xv) monocyclic type heteroaromatic ring-thio group (optionally having1-5 substituting moieties α₁ hereafter described), (xvi) amino group(optionally having 1 to 2 substituting moieties α₁ hereafter described)or (xvii) hydroxy group,

[0062] said substituting moiety α₁ is a (i) C₁-C₆ alkyl group, (ii)C₁-C₆ halogenoalkyl group, (iii) C₁-C₆ alkoxy group, (iv) halogen atom,(v) hydroxy group, (vi) cyano group, (vii) nitro group, (viii) C₃-C₁₀cycloalkyl group, (ix) C₆-C₁₀ aryl group (optionally having 1-5substituting moieties β hereafter described), (x) C₇-C₁₆ aralkyl group(optionally having 1-5 substituting moieties β hereafter described onthe aryl moiety thereof), (xi) C₁-C₇ aliphatic acyl group, (xii) C₄-C₁₁cycloalkylcarbonyl group, (xiii) C₇-C₁₁ arylcarbonyl group (optionallyhaving 1-5 substituting moieties β hereafter described), (xiv) C₈-C₁₇aralkylcarbonyl group (optionally having 1-5 substituting moieties βhereafter described on the aryl moiety thereof), (xv) monocyclic typeheteroaromatic ring-carbonyl group (optionally having 1-5 substitutingmoieties β hereafter described), (xvi) carbamoyl group, (xvii) C₇-C₁₁arylaminocarbonyl group (optionally having 1-5 substituting moieties βhereafter described on the aryl moiety thereof), (xviii) amino group(optionally having 1 to 2 substituting moieties β described hereafter)or (xix) carboxyl group,

[0063] said substituting moiety β is a (i) C₁-C₁₀ alkyl group, (ii)halogen atom, (iii) C₆-C₁₀ aryl group (optionally having 1-5substituting moieties γ hereafter described), (iv) C₇-C₁₆ aralkyl group(optionally having 1-5 substituting moieties γ hereafter described onthe aryl moiety thereof), (v) C₁-C₇ aliphatic acyl group, (vi) C₇-C₁₁arylcarbonyl group (optionally having 1-5 substituting moieties γhereafter described), (vii) C₈-C₁₇ aralkylcarbonyl group (optionallyhaving 1-5 substituting moieties γ hereafter described on the arylmoiety thereof), (viii) C₄-C₁₁ cycloalkylcarbonyl group, (ix) monocyclictype heteroaromatic ring-carbonyl group (optionally having 1-5substituting moieties γ hereafter described), (x) carbamoyl group or(xi) C₇-C₁₁ arylaminocarbonyl group (optionally having 1-5 substitutingmoieties γ hereafter described on the aryl moiety thereof), and

[0064] said substituting moiety γ is a C₁-C₆ alkyl group, C₁-C₆halogenoalkyl group, halogen atom or hydroxy group], theirpharmacologically acceptable esters, their pharmacologically acceptableamides or their pharmacologically acceptable salts. Further, Z₂O-groupin the general formula (II), Z₃S-group in the general formula (III) andZ₄ in the general formula (IV) is contained in the scope of Z₁ in thegeneral formula (I).

[0065] When R₁, R₂, R₃, R₄, X, Z₁, Z₃, α₁ and γ represent a “C₁-C₆ alkylgroup”, said group means a straight or branched alkyl group of 1 to 6carbon atoms. Examples of said group are methyl, ethyl, propyl,isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, s-pentyl,isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, hexyl,4-methylpentyl (isohexyl), 3-methylpentyl, 2-methylpentyl,1-methylpentyl (s-hexyl), 3,3-dimethylbutyl, 2,2-dimethylbutyl,1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl,2,3-dimethylbutyl or 2-ethylbutyl group. C₁-C₄ alkyl groups arepreferable, and C₁-C₂ alkyl groups are more preferable.

[0066] When R₁, R₂, R₃, R₄, Z₁, Z₃ and Z₄ represent a “C₆-C₁₀ aryl group(optionally having 1-5 substituting moieties α₁ described hereafter)”,when X, α₁ and α₂ represent a “C₆-C₁₀ aryl group (optionally having 1-5substituting moieties β hereafter described)”, when β is a “C₆-C₁₀ arylgroup (optionally having 1-5 substituting moieties γ hereafterdescribed)”, and when Z₂ is a “C₆-C₁₀ aryl group (optionally having 1-5substituting moieties α₂ described hereafter)”, said C₆-C₁₀ aryl groupillustratively includes phenyl, indenyl and naphthyl.

[0067] When R₁, R₂, R₃, R₄, Z₁ and Z₃ represent a “C₇-C₁₆ aralkyl group(optionally having 1-5 substituting moieties α₁ hereafter described onthe aryl moiety thereof)”, when X, α₁ and α₂ represent a “C₇-C₁₆ aralkylgroup (optionally having 1-5 substituting moieties β hereafter describedon the aryl moiety thereof)” and when β is a “C₇-C₁₆ aralkyl group(optionally having 1-5 substituting moieties γ hereafter described onthe aryl moiety thereof)”, said C₇-C₁₆ aralkyl group means a C₁-C₆ alkylgroup which is substituted by said C₆-C₁₀ aryl group. Examples of saidaralkyl moiety are benzyl, naphthylmethyl, indenylmethyl, 1-phenethyl,2-phenethyl, 1-naphthylethyl, 2-naphthylethyl, 1-phenylpropyl,2-phenylpropyl, 3-phenylpropyl, 1-naphthylpropyl, 2-naphthylpropyl,3-naphthylpropyl, 1-phenylbutyl, 2-phenylbutyl, 3-phenylbutyl,4-phenylbutyl, 1-naphthylbutyl, 2-naphthylbutyl, 3-naphthylbutyl,4-naphthylbutyl, 5-phenylpentyl, 5-naphthylpentyl, 6-phenylhexyl and6-naphthylhexyl.

[0068] When R₁, R₂ and R₃ represent a “C₁-C₆ alkylsulfonyl group”, saidgroup means a group in which said C₁-C₆ alkyl group is bonded to thesulfonyl moiety. Examples of said group are methanesulfonyl,ethanesulfonyl, propanesulfonyl, isopropanesulfonyl, butanesulfonyl,isobutanesulfonyl, s-butanesulfonyl, t-butanesulfonyl, pentanesulfonyl,isopentanesulfonyl, 2-methylbutanesulfonyl, neopentanesulfonyl,1-ethylpropanesulfonyl, hexanesulfonyl, 4-methylpentanesulfonyl,3-methylpentanesulfonyl, 2-methylpentanesulfonyl,3,3-dimethylpentanesulfonyl, 2,2-dimethylbutanesulfonyl,1,1-dimethylbutanesulfonyl, 1,2-dimethylbutanesulfonyl,1,3-dimethylbutanesulfonyl, 2,3-dimethylbutanesulfonyl and2-ethylbutanesulfonyl. C₁-C₄ alkylsulfonyl groups are preferable, C₁-C₂alkylsulfonyl groups are more preferable, and methanesulfonyl is themost preferable.

[0069] When R₁, R₂ and R₃ represent a “C₁-C₆ halogenoalkylsulfonylgroup”, said group means a group in which the alkyl moiety of said C₁-C₆alkylsulfonyl group is substituted by one or more halogen atoms.Examples of said group are trifluoromethanesulfonyl,trichloromethanesulfonyl, difluoromethanesulfonyl,dichloro-methanesulfonyl, dibromomethanesulfonyl, fluoromethanesulfonyl,2,2,2-trifluoroethanesulfonyl, 2,2,2-trichloroethanesulfonyl,2-bromoethanesulfonyl, 2-chloroethanesulfonyl, 2-fluoroethanesulfonyl,2-iodoethanesulfonyl, 3-chloropropanesulfonyl, 4-fluorobutanesulfonyl,6-iodohexanesulfonyl and 2,2-dibromethanesulfonyl.

[0070] C_(l)-C₄ halogenoalkylsulfonyl groups are preferable, C₁-C₂halogenoalkylsulfonyl groups are more preferable, andtrifluoromethanesulfonyl is the most preferable.

[0071] When R₁, R₂ and R₃ represent a “C₆-C₁₀ arylsulfonyl group(optionally having 1-5 substituting moieties α₁ hereafter described)”,said C₆-C₁₀ arylsulfonyl moiety means a group in which said C₆-C₁₀ arylgroup is bonded to a sulfonyl moiety. Examples of said C₆-C₁₀arylsulfonyl moiety are phenylsulfonyl, indenylsulfonyl andnaphthylsulfonyl.

[0072] When R₁, R₂ and R₃ represent a “C₇-C₁₆ aralkylsulfonyl group(optionally having 1-5 substituting moieties α₁ hereafter described onthe aryl moiety thereof)”, said C₇-C₁₆ aralkylsulfonyl moiety free ofthe substituting moiety means a group in which said C₇-C₁₆ aralkyl isbonded to a sulfonyl moiety. Examples of said C₇-C₁₆ aralkylsulfonylmoiety are benzylsulfonyl, naphthylmethylsulfonyl,indenylmethylsulfonyl, 1-phenethylsulfonyl, 2-phenethylsulfonyl,1-naphthylethylsulfonyl, 2-naphthylethylsulfonyl,1-phenylpropylsulfonyl, 2-phenylpropylsulfonyl, 3-phenylpropylsulfonyl,1-naphthylpropylsulfonyl, 2-naphthylpropylsulfonyl,3-naphthylpropylsulfonyl, 1-phenylbutylsulfonyl, 2-phenylbutylsulfonyl,3-phenylbutylsulfonyl, 4-phenylbutylsulfonyl, 1-naphthylbutylsulfonyl,2-naphthylbutylsulfonyl, 3-naphthylbutylsulfonyl,4-naphthylbutylsulfonyl, 5-phenylpentylsulfonyl,5-naphthylpentylsulfonyl, 6-phenylhexylsulfonyl and6-naphthylhexylsulfonyl.

[0073] When W₁ and W₂ represent a “C₁-C₆ alkylene group”, said groupmeans a straight or branched chain alkylene group containing 1 to 8carbon atoms. Examples of said group are methylene, methylmethylene,ethylene, propylene, trimethylene, 1-methylethylene, tetramethylene,1-methyltrimethylene, 2-methyltrimethylene, 3-methyltrimethylene,1-methylpropylene, 1,1-dimethylethylene, pentamethylene,1-methyltetramethylene, 2-methyltetramethylene, 3-methyltetramethylene,4-methyltetramethylene, 1,1-dimethyltrimethylene,2,2-dimethyltrimethylene, 3,3-dimethyltrimethylene, hexamethylene,1-methylpentamethylene, 2-methylpentamethylene, 3-methylpentamethylene,4-methylpentamethylene, 5-methylpentamethylene,1,1-dimethyltetramethylene, 2,2-dimethyltetramethylene,3,3-dimethyltetramethylene, 4,4-dimethyltetramethylene, heptamethylene,1-methylhexamethylene, 2-methylhexamethylene, 5-methylhexamethylene,3-ethylpentamethylene, octamethylene, 2-methylheptamethylene,5-methylheptamethylene, 2-ethylhexamethylene,2-ethyl-3-methylpentamethylene and 3-ethyl-2-methylpentamethylene. Thestraight chain type C₁-C₆ alkylene groups are preferable, the straightchain type C₁-C₄ alkylene groups are more preferable, and the straightchain type C₁-C₂ alkylene groups are the most preferable.

[0074] When X, α₁ and γ represent a “C₁-C₆ halogenoalkyl group”, saidgroup means a group in which said C₁-C₆ alkyl group is substituted byone or more halogen atoms. Examples of said group are trifluoromethyl,trichloromethyl, difluoromethyl, dichloromethyl, dibromomethyl,fluoromethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, 2-bromoethyl,2-chloroethyl, 2-fluoroethyl, 2-iodoethyl, 3-chloropropyl,4-fluorobutyl, 6-iodohexyl, and 2,2-dibromethyl. C₁-C₄ halogenoalkylgroups are preferable, C₁-C₂ halogenoalkyl groups are more preferable,and trifluoromethyl is the most preferable.

[0075] When X, Z₁, Z₄ and α₁ represent a “C₁-C₆ alkoxy group”, saidgroup means a group in which said C₁-C₆ alkyl group is bonded to oxygenatom. Examples of said group are methoxy, ethoxy, propoxy, isopropoxy,butoxy, isobutoxy, s-butoxy, t-butoxy, pentoxy, isopentoxy,2-methylbutoxy, neopentoxy, 1-ethylpropoxy, hexyloxy, 4-methylpentoxy,3-methylpentoxy, 2-methylpentoxy, 3,3-dimethylbutoxy,2,2-dimethylbutoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy,1,3-dimethylbutoxy, 2,3-dimethylbutoxy, and 2-ethylbutoxy. C₁-C₄ alkoxygroups are preferable, C₁-C₂ alkoxy groups are more preferable, andmethoxy is the most preferable.

[0076] When X, Z₁, Z₄, α₁, β and γ represent a “halogen atom”, saidgroup means illustratively a fluorine atom, chlorine atom, bromine atomand iodine atom. Fluorine atom, chlorine atom and bromine atom arepreferable, and fluorine atom and chlorine atom are more preferable.

[0077] When X, Z₃, α₁ and α₂ represent a “C₃-C₁₀ cycloalkyl group”, saidgroup means a 3 to 10 member saturated cyclic ring type hydrocarbon.Examples of said group are cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, norbornyl and adamantyl. Cyclopropyl,cyclohexyl and adamantyl are preferable, and adamantyl is morepreferable.

[0078] When X, α₁, α₂ and β represent a “C₁-C₇ aliphatic acyl group”,said group involves illustratively formyl, acetyl, propionyl, butyryl,isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, acryloyl,methacryloyl and crotonoyl. C₁-C₅ aliphatic acyl groups are preferable,C₁-C₃ aliphatic acyl groups are more preferable, and acetyl is the mostpreferable.

[0079] When X, α₁, α₂ and β represent a “C₄-C₁₁ cycloalkylcarbonylgroup”, said group means a group in which said C₃-C₁₀ cycloalkyl groupis bonded to a carbonyl group. Examples of said group arecyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl,cyclohexylcarbonyl, cycloheptylcarbonyl, norbornylcarbonyl andadamantylcarbonyl. C₄-C₇ cycloalkylcarbonyl groups are preferable. WhenX, Z₂, α₁ and α₂ represent a “C₇-C₁₁ arylcarbonyl group (optionallyhaving 1-5 substituting moieties β hereafter described)”, and when βrepresents “C₇-C₁₁ arylcarbonyl group (optionally having 1-5substituting moieties γ hereafter described)”, said C₇-C₁₁ arylcarbonylmoiety means a group in which said C₆-C₁₀ aryl group is bonded to acarbonyl group. Examples of said C₇-C₁₁ arylcarbonyl moiety are benzoyl,1-indanecarbonyl, 2-indanecarbonyl and 1- or 2-naphthoyl. When X, α₁ andα₂ represent a “C₈-C₁₇ aralkylcarbonyl group (optionally having 1-5substituting moieties β hereafter described on the aryl moiety thereof)”and when β represents “C₈-C₁₇ aralkylcarbonyl group (optionally having1-5 substituting moieties γ hereafter described on the aryl moietythereof)”, said C₈-C₁₇ aralkylcarbonyl moiety means a group in whichsaid C₇-C₁₆ aralkyl group is bonded to carbonyl group. Examples of saidC₈-C₁₇ aralkylcarbonyl moiety are phenylacetyl, 3-phenylpropionyl,4-phenylbutyryl, 5-phenylpentanoyl, 6-phenylhexanoyl, naphthylacetyl,4-naphthylbutyryl and 6-naphthylhexanoyl.

[0080] When X, α₁ and α₂ represent a “monocyclic type heteroaromaticring-carbonyl group (optionally having 1-5 substituting moieties βhereafter described)” and when β represents a “monocyclic typeheteroaromatic ring-carbonyl group (optionally having 1-5 substitutingmoieties γ hereafter described)”, said monocyclic type heteroaromaticring-carbonyl moiety means a group in which a 5-7 member heteroaromaticring containing 1-3 heteroatoms selected from the group consisting ofoxygen, nitrogen and sulfur atoms is bonded to a carbonyl group.Examples of said monocyclic type heteroaromatic ring-carbonyl moiety are5-member heteroaromatic ring-carbonyl groups such as furylcarbonyl,thienylcarbonyl, pyrrolylcarbonyl, pyrazolylcarbonyl,imidazolylcarbonyl, oxazolylcarbonyl, isoxazolylcarbonyl,thiazolylcarbonyl, isothiazolylcarbonyl, 1,2,3-oxadiazolylcarbonyl,triazolylcarbonyl and thiadiazolylcarbonyl; 6-member heteroaromaticring-carbonyl groups such as pyranylcarbonyl, nicotinoyl, isonicotinoyl,pyridazinylcarbonyl, pyrimidinylcarbonyl and pyrazinylcarbonyl; and7-member heteroaromatic ring-carbonyl groups such as azepinylcarbonyl,etc.

[0081] When X, α₁ and α₂ represent a “C₇-C₁₁ arylaminocarbonyl group(optionally having 1-5 substituting moieties β hereafter described onthe aryl moiety thereof)” and when 62 represents a “C₇-C₁₁arylaminocarbonyl group (optionally having 1-5 substituting moieties γhereafter described on the aryl moiety thereof)”, said C₇-C₁₁arylaminocarbonyl moiety means a group in which the amino group of theaminocarbonyl group is substituted by said C₆-C₁₀ aryl group. Examplesof said C₇-C₁₁ arylaminocarbonyl moiety are phenylaminocarbonyl,indenylaminocarbonyl and naphthylaminocarbonyl.

[0082] When Z₁ and Z₄ represent a “C₁-C₆ alkylthio group”, it means agroup in which said C₁-C₆ alkyl group is bonded to a sulfur atom.Examples of said group are methylthio, ethylthio, propylthio,isopropylthio, butylthio, isobutylthio, s-butylthio, t-butylthio,pentylthio, isopentylthio, 2-methylbutylthio, neopentylthio,1-ethylpropylthio, hexylthio, 4-methylpentylthio, 3-methylpentylthio,2-methylpentylthio, 3,3-dimethylbutylthio, 2,2-dimethylbutylthio,1,1-dimethylbutylthio, 1,2-dimethylbutylthio, 1,3-dimethylbutylthio,2,3-dimethylbutylthio and 2-ethylbutylthio. C₁-C₄ alkylthio groups arepreferable, C₁-C₂ alkylthio groups are more preferable, and methylthiogroups are the most preferable.

[0083] When Z₁ and Z₄ represent a “C₆-C₁₀ aryloxy group (optionallyhaving 1-5 substituting moieties α₁ hereafter described)”, said C₆-C₁₀aryloxy moiety means a group in which said C₆-C₁₀ aryl group issubstituted by an oxygen atom. Examples thereof are phenoxy, indenyloxyand naphthyloxy.

[0084] When Z₁ and Z₄ represent a “C₇-C₁₆ aralkyloxy group (optionallyhaving 1-5 substituting moieties α₁ hereafter described on the arylmoiety thereof)”, said C₇-C₁₆ aralkyloxy moiety means a group in whichsaid C₇-C₁₆ aralkyloxy is substituted by an oxygen atom. Examples ofsaid C₇-C₁₆ aralkyloxy moiety are benzyloxy, naphthylmethloxy,indenylmethyloxy, 1-phenethyloxy, 2-phenethyloxy, 1-naphthylethyloxy,2-naphthylethyloxy, 1-phenylpropyloxy, 2-phenylpropyloxy,1-phenylpropyloxy, 2-phenylpropyloxy, 3-phenylpropyloxy,1-naphthylpropyloxy, 2-naphthylpropyloxy, 3-naphthylpropyloxy,1-phenylbutyloxy, 2-phenylbutyloxy, 3-phenylbutyloxy, 4-phenylbutyloxy,1-naphthylbutyloxy, 2-naphthylbutyloxy, 3-naphthylbutyloxy,4-naphthylbutyloxy, 5-phenylpentyloxy, 5-naphthylpentyloxy,6-phenylhexyloxy and 6-naphthylhexyloxy.

[0085] When Z₁ and Z₄ represent “C₃-C₁₀ cycloalkyloxy group”, said groupmeans a group in which said C₃-C₁₀ cycloalkyl group is substituted by anoxygen atom. Examples of said group are cyclopropyloxy, cyclobutyloxy,cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, norbornyloxy andadamantyloxy. C₃-C₆ cycloalkyloxy groups are preferable, and C₅-C₆cycloalkyloxy groups are more preferable.

[0086] When Z₁ and Z₄ represent a “C₃-C₁₀ cycloalkylthio group”, saidgroup means a group in which said C₃-C₁₀ cycloalkyl group is substitutedby a sulfur atom. Examples of said group are cyclopropylthio,cyclobutylthio, cyclopentylthio, cyclohexylthio, cycloheptylthio,norbornylthio and admantylthio. C₃-C₆ cycloalkylthio groups arepreferable, and C₅-C₆ cycloalkylthio groups are more preferable.

[0087] When Z₂ and Z₃ represent a “saturated heterocyclic ring group(optionally having 1-5 substituting moieties α₁ hereafter described)”,said saturated heterocyclic ring moiety means a group in which a 4-7member saturated heterocyclic ring group contains at least one ring atomselected from nitrogen, oxygen and sulfur atoms. Examples of saidsaturated heterocyclic ring moiety are 4-member saturated heterocyclicrings such as azetidyl, etc.; 5-member saturated heterocyclic rings suchas pyrrolidyl, tetrahydrofuranyl, tetrahydrothiophenyl, imidazolidyl,oxazolidyl, isoxazolidyl, thiazolidyl, isothiazolidyl, etc.; 6-membersaturated heterocyclic rings such as piperidino, tetrahydropyranyl,tetrahydrothiopyranyl, piperazino, morpholino, thiomorpholino, etc.; and7-member saturated heterocyclic ring groups such as homopiperazino, etc.

[0088] When Z₁ and Z₄ represent a “saturated heterocyclic ring-oxy group(optionally having 1-5 substituting moieties α₁ hereafter described)”,said saturated heterocyclic ring-oxy moiety means a group in which saidsaturated heterocyclic ring is bonded to oxygen atom. Examples of saidsaturated heterocyclic ring-oxy moiety are 4-member saturatedheterocyclic ring-oxy groups such as azetidyloxy, etc.; 5-membersaturated heterocyclic ring-oxy groups such as pyrrolidyloxy,tetrahydrofuranyloxy, tetrahydrothiophenyloxy, imidazolidyloxy,oxazolidyloxy, isoxazolidyloxy, thiazolidyloxy, isothiazolidyloxy, etc.;6-member saturated heterocyclic ring-oxy groups such as piperidinoxy,tetrahydropyranyloxy, tetrahydrothiopyranyloxy, piperazinoxy,morpholinoxy, thiomorpholinoxy, etc.; and 7-member saturatedheterocyclic ring-oxy groups such as homopiperazinoxy, etc.

[0089] When Z₁ and Z₃ represent a “monocyclic type heteroaromaticring-oxy group (optionally having 1-5 substituting moieties α₁ hereafterdescribed)”, said monocyclic heteroaromatic ring-oxy moiety means agroup in which said 5-7 member heteroaromatic ring containing 1-3heteroatom(s) selected from the group consisting of oxygen, nitrogen andsulfur atoms is bonded to an oxygen atom. Examples of said saturatedheterocyclic ring-oxy moiety are 5-member heteroaromatic ring-oxy groupssuch as furyloxy, thienyloxy, pyrrolyloxy, pyrazolyloxy, imidazolyloxy,oxazolyloxy, isoxazolyloxy, thiazolyloxy, isothiazolyloxy,1,2,3-oxadiazolyloxy, triazolyloxy, tetrazolyloxy, thiadiazolyloxy,etc.; 6-member heteroaromatic ring-oxy groups such as pyranyloxy,pyridyloxy, pyridazinyloxy, pyrimidinyloxy, pyrazinyloxy, etc.; and7-member heterocyclic ring-oxy groups such as azepinyloxy, etc.

[0090] When Z₁ and Z₄ represent a “C₆-C₁₀ arylthio group (optionallyhaving 1-5 substituting moieties α₁ hereafter described on the arylmoiety thereof)”, said C₆-C₁₀ arylthio moiety means a group in whichsaid C₆-C₁₀ aryl group is substituted by a sulfur atom. Examples of saidC₆-C₁₀ arylthio moiety are phenylthio, indenylthio and naphthylthio.

[0091] When Z₁ and Z₄ represent a “C₇-C₁₆ aralkylthio group (optionallyhaving 1-5 substituting moieties α₁ hereafter described)”, said C₇-C₁₆aralkylthio moiety means a group in which said C₇-C₁₆ aralkylthio groupis substituted by a sulfur atom. Examples of said C₇-C₁₆ aralkylthiomoiety are benzylthio, naphthylmethylthio, indenylmethylthio,1-phenethylthio, 2-phenethylthio, 1 -naphthylethylthio,2-naphthylethylthio, 1-phenylpropylthio, 2-phenylpropylthio,3-phenylpropylthio, 1-naphthylpropylthio, 2-naphthylpropylthio,3-naphthylpropylthio, 1-phenylbutylthio, 2-phenylbutylthio,3-phenylbutylthio, 4-phenylbutylthio, 1-naphthylbutylthio,2-naphthylbutylthio, 3-naphthylbutylthio, 4-naphthylbutylthio,5-phenylpentylthio, 5-naphthylpentylthio, 6-phenylhexylthio and6-naphthylhexylthio.

[0092] When Z₁ and Z₄ represent a “saturated heterocyclic ring-thiogroup (optionally having 1-5 substituting moieties α₁ hereafterdescribed)”, said saturated heterocyclic ring-thio moiety means a groupin which said saturated heterocyclic ring is bonded to a sulfur atom.Examples of said saturated heterocyclic ring-thio moiety are 4-membersaturated heterocyclic ring-oxy groups such as azetidylthio, etc.;5-member saturated heterocyclic ring-thio groups such as pyrrolidylthio,tetrahydrofuranyl, imidazolidylthio, oxazolidylthio, isoxazolidylthio,thiazolidylthio, isothiazolidylthio, etc.; 6-member saturatedheterocyclic ring-thio groups such as piperidinylthio,tetrahydropyranylthio, tetrahydrothiopyranylthio, piperazinylthio,morpholylthio, thiomorpholylthio, etc.; and 7-member saturatedheterocyclic ring-thio groups such as homopiperazinothio, etc.

[0093] When Z₁ and Z₄ represent a “monocyclic type heteroaromaticring-thio group (optionally having 1-5 substituting moieties α₁hereafter described)”, said monocyclic heteroaromatic ring-thio moietymeans a group in which said 5-7 member heteroaromatic ring containing1-3 heteroatom(s) selected from the group consisting of oxygen, nitrogenand sulfur atoms is bonded to a sulfur atom. Examples of said saturatedheterocyclic ring-thio moiety are 5-member heteroaromatic ring-thiogroups such as furylthio, thienylthio, pyrrolylthio, pyrazolylthio,imidazolylthio, oxazolylthio, isoxazolylthio, thiazolylthio,isothiazolyltho, 1,2,3-oxadiazolylthio, triazolylthio, tetrazolylthio,thiadiazolylthio, etc.; 6-member heteroaromatic ring-thio groups such aspyranylthio, pyridylthio, pyridazinylthio, pyrimidinylthio,pyrazinylthio, etc.; and 7-member heterocyclic ring-thio groups such asazepinylthio, etc.

[0094] When β represents a “C₁-C₁₀ alkyl group”, said group means astraight chain or branched chain alkyl group of 1-10 carbon atoms.Examples of said group are heptyl, 1-methylhexyl, 2-methylhexyl, nonyl,3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 1-propylbutyl,4,4-dimethylpentyl, octyl, 1-methylheptyl, 2-methylheptyl,3-methylheptyl, 4-methylheptyl, 5-methylheptyl, 6-methylheptyl,1-propylpentyl, 2-ethylhexyl, 5,5-dimethylhexyl, nonyl, 3-methyloctyl,4-methyloctyl, 5-methyloctyl, 6-methyloctyl, 1-propylhexyl,2-ethylheptyl, 6,6-dimethylheptyl, decyl, 1-methylnonyl, 3-methylnonyl,8-methylnonyl, 3-ethyloctyl, 3,7-dimethyloctyl and 7,7-dimethyloctyl, inaddition to those illustrated in the definition of said C₁-C₆ alkylgroup. C₁-C₆ alkyl groups are preferable, C₁-C₄ alkyl groups are morepreferable, and C₁-C₂ alkyl groups are the most preferable.

[0095] When the substituting moiety β represents a “C₆-C₁₀ aryl group(optionally having 1-5 substituting moieties γ), in view of thedefinition of said substituting moiety γ, examples of said group havingthe substituting moiety γ are 4-methylphenyl, 4-methylnaphthyl,3,4-dimethylphenyl, 2,3,4-trimethylphenyl, 4-propylphenyl,4-propylnaphthyl, 2-, 3- or 4-trifluoromethylphenyl, 2-, 3- or4-trifluoromethylnaphthyl, 3,4-ditrifluoromethylphenyl,2,3,4-tritrifluoromethylphenyl, 4-tetrafluoropropylnaphthyl,4-fluorophenyl, 4-fluoronaphthyl, 3,4-difluorophenyl,2,3,4-trifluorophenyl, 4-hydroxyphenyl, 4-hydroxynaphthyl,3,4-dihydroxyphenyl and 2,3,4-trihydroxyphenyl. As to said group, C₆-C₁₀aryl groups (optionally having 1-3 substituting moieties γ) arepreferable, phenyl groups (optionally having 1-3 substituting moietiesγ) are more preferable, and phenyl or 4-trifluoromethylphenyl are themost preferable.

[0096] When the substituting moiety β represents a “C₇-C₁₆ aralkyl group(optionally having 1-5 substituting moieties γ on the aryl moietythereof)”, examples of said group having such a substituting moiety are4-methylbenzyl, 2,3,4-trimethylbenzyl, 4-methylphenethyl,2,3,4-trimethylphenethyl, 4-(4-methylphenyl)butyl, 2-, 3- or4-trifluoromethylbenzyl, 3,4-ditrifluoromethylbenzyl,2,3,4-tritrifluoromethylbenzyl, 4-tetrafluoropropylbenzyl,4-trifluoromethylphenethyl, 3,4-ditrifluoromethylphenethyl,2,3,4-tritrifluoromethylphenethyl, 4-tetrafluoropropylphenethyl,4-(4-trifluoromethylphenyl)butyl, 4-(4-tetrafluoropropyl)butyl,6-(4-trifluoromethylphenyl)hexyl, 6-(4-tetrafluoropropylphenyl)hexyl,2-, 3- or 4-trifluoromethylnaphthylmethyl,4-tetrafluoropropylnaphthylmethyl, 4-(4-trifluoromethylnaphthyl)butyl,4-(4-tetrafluoropropylnaphthyl)butyl, 4-fluorobenzyl,2,3,4-trifluorobenzyl, 4-fluorophenethyl, 2,3,4-trifluorophenethyl,4-(4-fluorophenyl)butyl, 4-hydroxybenzyl, 2,3,4-trihydroxybenzyl,4-hydroxyphenethyl, 2,3,4-trihydroxyphenethyl and4-(4-hydroxyphenyl)butyl. As to said group, C₇-C₁₆ aralkyl groups(optionally having 1-3 substituting moieties γ on the aryl moietythereof) are preferable, phenyl-C₁-C₆ alkyl groups (optionally having1-3 substituting moieties γ on the phenyl moiety) are more preferable,further phenyl-C₁-C₆ alkyl groups (optionally having one trifluoromethylgroup on the phenyl moiety) are yet more preferable, and phenyl-C₁-C₂alkyl groups (optionally having one trifluoromethyl group on the phenylmoiety) are the most preferable.

[0097] When the substituting moiety β represents a “C₇-C₁₁ arylcarbonylgroup (optionally having 1-5 substituting moieties γ)”, examples of saidgroup having such a substituting moiety are 4-methylbenzoyl, 1- or2-(5-methyl)naphthoyl, 4-trifluoromethylbenzoyl,4-tetrafluoropropylbenzoyl, 1-(5-trifluoromethylindane)carbonyl,2-(5-trifluoromethylindane)carbonyl,2-(6-trifluoromethylindane)carbonyl, 1- or2-(5-trifluoromethyl)naphthoyl, 4-fluorobenzoyl, 1- or2-(5-fluoro)naphthoyl, 4-hydroxybenzoyl and 1- or2-(5-hydroxy)naphthoyl. As said group, C₇-C₁₁ arylcarbonyl groups(optionally having 1-3 substituting moieties γ) are preferable, benzoylgroups (optionally having 1-3 substituting moieties γ) are morepreferable, further benzoyl groups (optionally having one substitutingmoiety γ) are yet more preferable, and benzoyl groups (optionally havingone substituting moiety, trifluoromethyl) are the most preferable.

[0098] When the substituting moiety β represents a “C₈-C₁₇aralkylcarbonyl group (optionally having 1-5 substituting moieties onthe aryl moiety thereof”, examples of said group having such asubstituting moiety are 4-methylphenylacetyl, 4-(4-methyl)phenylbutyryl,6-(methylnaphthyl)hexanoyl, 2-, 3- or 4-trifluoromethylphenylacetyl,4-tetrafluoropropylphenylacetyl, 4-(4-trifluoromethyl)phenylbutyryl,6-(4-trifluoromethyl)phenylhexanoyl, 4-trifluoromethylnaphthylacetyl,6-(trifluoromethylnaphthyl)hexanoyl, 4-fluorophenylacetyl,4-(4-fluoro)phenylbutyryl, 6-(fluoronaphthyl)hexanoyl,4-hydroxyphenylacetyl, 4-(4-hydroxy)phenylbutyryl and6-(hydroxynaphthyl)hexanoyl. As to said group, C₈-C₁₇ aralkylcarbonylgroups (optionally having 1-3 substituting moieties γ on the arylmoiety) are preferable, phenyl-C₁-C₆ alkylcarbonyl groups (optionallyhaving 1-3 substituting moieties γ on the aryl moiety) are morepreferable, further phenyl-C₁-C₆ alkylcarbonyl groups (optionally havingone substituting moiety, C₁-C₆ halogenoalkyl on the aryl moiety) arestill more preferable, furthermore phenyl-C₁-C₆ alkylcarbonyl groups(optionally having one substituting moiety, trifluoromethyl on the arylmoiety) are yet more preferable, and phenylacetyl or4-trifluoromethylphenylacetyl are the most preferable.

[0099] When the substituting moiety β represents a “monocyclic typeheteroaromatic ring-carbonyl group (optionally having 1-5 substitutingmoieties γ)”, examples of the group having such a substituting moietyare methylfurylcarbonyl, methylthienylcarbonyl, methylpyrrolylcarbonyl,methylnicotinoyl, trifluoromethylfurylcarbonyl,trifluoromethylthienylcarbonyl, trifluoromethylpyrrolylcarbonyl,trifluoromethyloxazolylcarbonyl, trifluoromethylthiazolylcarbonyl,trifluoromethylnicotinoyl, tetrafluoropropylfurylcarbonyl,tetrafluoropropylthienylcarbonyl, tetrafluoropropylpyrrolylcarbonyl,fluorofurylcarbonyl, fluorothienylcarbonyl, fluoropyrrolylcarbonyl,fluoronicotinoyl, hydroxyfurylcarbonyl, hydroxythienylcarbonyl,hydroxypyrrolylcarbonyl and hydroxynicotinyol. As to said group,monocyclic type heteroaromatic ring-carbonyl groups (optionally having1-3 substituting moieties γ) are preferable, monocyclic typeheteroaromatic ring-carbonyl groups (optionally having one substitutingmoiety γ) are more preferable, further monocyclic type heteroaromaticring-carbonyl groups (optionally having one substituting moiety,trifluoromethyl) are still more preferable, furthermore 5- or 6-membermonocyclic type heteroaromatic ring-carbonyl groups (optionally havingone substituting moiety, trifluoromethyl) are yet more preferable, andfurylcarbonyl, thienylcarbonyl, pyrrolylcarbonyl or nicotinoyl are themost preferable. When the substituting moiety β represents a “C₇-C₁₁arylaminocarbonyl group (optionally having 1-5 substituting moieties γon the aryl moiety thereof)”, examples of said group having such asubstituting moiety are 4-methylphenylcarbamoyl,2,3,4-trimethylphenylcarbamoyl, 1- or 2-(6- or7-methylnaphthyl)carbamoyl, 2-, 3- or 4-trifluoromethylphenylcarbamoyl,4-tetrafluoropropylphenylcarbamoyl, 3,4-difluoromethylphenylcarbamoyl,2,3,4-tritrifluoromethylphenylcarbamoyl, 1- or 2-(6- or7-trifluoromethylnaphthyl)carbamoyl,2-(6-tetrafluoropropylnaphthyl)carbamoyl, 4-fluorophenylcarbamoyl,2,3,4-trifluorophenylcarbamoyl, 1- or 2-(6- or7-fluoronaphthyl)carbamoyl, 4-hydroxyphenylcarbamoyl,2,3,4-trihydroxyphenylcarbamoyl and 1- or 2-(6- or7-hydroxynaphthyl)carbamoyl. As to said group, C₇-C₁₁ arylaminocarbonylgroups (optionally having 1-3 substituting moieties γ on the arylmoiety) are preferable, phenylaminocarbonyl groups (optionally having1-3 substituting moieties γ on the phenyl moiety) are more preferable,further phenylaminocarbonyl groups (optionally having 1-3 C₁-C₆halogenoalkyl groups as the substituting moiety γ on the phenyl moiety)are more preferable, and furthermore phenylaminocarbonyl groups(optionally having one trifluoromethyl group as the substituting moiety)are the most preferable.

[0100] When X, α₁ and α₂ represent a “C₆-C₁₀ aryl group (optionallyhaving 1-5 substituting moieties β) in view of the definition of said β,examples of said group having such a substituting moiety aremethylphenyl, acetylphenyl, benzoylphenyl, biphenylyl, methylbiphenylyl,methylnaphthyl, acetylnaphthyl and benzoylnaphthyl. As to said group,C₆-C₁₀ aryl groups (optionally having 1-3 substituting moieties β) arepreferable, phenyl groups (optionally having 1-3 substituting moietiesβ) are more preferable, further phenyl groups (optionally having 1 or 2substituting moieties β) are yet more preferable, and furthermore phenylgroups (optionally having 1 substituting moiety β) are the mostpreferable.

[0101] When X, α₁ and α₂ represent a “C₇-C₁₆ aralkyl group (optionallyhaving 1-5 substituting moieties β on the aryl moiety)”, examples ofsaid group having such a substituting moiety are methylbenzyl,acetylbenzyl, benzoylbenzyl, biphenylylmethyl, methylbiphenylylmethyl,methylnaphthylmethyl, acetylnaphthylmethyl, benzoylnaphthylmethyl,methylphenethyl, acetylphenethyl, methylnaphthylethyl,acetylnaphthylethyl, methylphenylbutyl, acetylphenylbutyl,methylnaphthylbutyl and acetylnaphthylbutyl. As to said group, C₇-C₁₆aralkyl groups (optionally having 1-3 substituting moieties β on thearyl moeity) are preferable, phenyl-C₁-C₆ alkyl groups (optionallyhaving 1-3 substituting moieties β on the phenyl moiety) are morepreferable, further phenyl-C₁-C₄ alkyl groups (optionally having 1 or 2substituting moieties β on the phenyl moiety) are yet more preferable,and furthermore benzyl or phenethyl groups (optionally having onesubstituting moiety β) are the most preferable.

[0102] When X, α₁ and α₂ represent a “C₇-C₁₁ arylcarbonyl group(optionally having 1-5 substituting moieties β)”, examples of said grouphaving such a substituting moiety are methylbenzoyl, biphenylylcarbonyl,acetylbenzoyl, carbamoylbenzoyl, 4-trifluoromethylphenylcarbamoylbenzoyland trifluoronaphthylcarbonyl. As to said group, C₇-C₁₁ arylcarbonylgroups (optionally having 1-3 substituting moieties β) are preferable,benzoyl groups (optionally having 1-3 substituting moieties β) are morepreferable, further benzoyl groups (optionally having 1 or 2substituting moieties β) are yet more preferable, and furthermorebenzoyl groups (optionally having one substituting moiety β) are themost preferable.

[0103] When X, α₁ and α₂ represent a “C₈-C₁₇ aralkylcarbonyl group(optionally having 1-5 substituting moieties β on the aryl moietythereof), examples of said group having such a substituting moiety aremethylphenylacetyl, acetylphenylacetyl, benzoylphenylacetyl,biphenylylacetyl, carbamoylphenylacetyl,(4-trifluoromethylphenylcarbamoyl)phenylacetyl, 4-(methylphenyl)butyryl,4-[(4-trifluoromethylphenylcarbamoyl)phenyl]butyryl,methylnaphthylacetyl and carbamoylnaphthylacetyl. As to said group,C₈-C₁₇ aralkylcarbonyl groups (optionally having 1-3 substitutingmoieties β on the aryl moiety) are preferable, phenyl-C₂-C₇alkylcarbonyl groups (optionally having 1-3 substituting moieties β onthe phenyl moiety) are more preferable, further phenyl-C₂-C₇alkylcarbonyl groups (optionally having one substituting moiety β on thephenyl moiety) are yet more preferable, and furthermore phenylacetylgroups (optionally having one substituting moiety β on the phenylmoiety) are the most preferable.

[0104] When X, α₁ and α₂ represent a “monocyclic type heteroaromaticring-carbonyl group (optionally having 1-5 substituting moieties βhereafter described)”, examples of said group are methylfurylcarbonyl,methylthienylcarbonyl, methylpyrrolylcarbonyl, methyloxazolylcarbonyl,methylthiazolylcarbonyl, methyltriazolylcarbonyl, methylpyranylcarbonyl,methylnicotinoyl, methylpyridazinylcarbonyl, methylpyrimidinylcarbonyl,acetylfurylcarbonyl, acetylthienylcarbonyl, acetylpyrrolylcarbonyl,acetyloxazolylcarbonyl, acetylthiazolylcarbonyl, acetylnicotinoyl,carbamoylfurylcarbonyl, carbamoylthienylcarbonyl,carbamoylpyrrolylcarbonyl, carbamoyloxazolylcarbonyl,carbamoylthiazolylcarbonyl and carbamoylnicotinoyl. As to said group,monocyclic type heteroaromatic ring-carbonyl groups (optionally having1-3 substituting moieties β) are preferable, further monocyclic typeheteroaromatic ring-carbonyl groups (optionally having 1 or 2substituting moieties β) are more preferable, furthermore 5- or 6-membermonocyclic type heteroaromatic ring-carbonyl groups (optionally having 1or 2 substituting moieties β) are yet more preferable, and 5- or6-member monocyclic type heteroaromatic ring-carbonyl groups (optionallyhaving one substituting moiety β) are the most preferable.

[0105] When X, α₁ and α₂ represent a “C₇-C₁₁ arylaminocarbonyl group(optionally having 1-5 substituting moieties β hereafter described onthe aryl moiety thereof)”, examples of said group having such asubstituting moiety are methylphenylcarbonyl, biphenylylcarbamoyl,acetylphenylcarbamoyl, methylnaphthylcarbamoyl, andacetylnaphthylcarbamoyl. As to said group, C₇-C₁₁ arylaminocarbonylgroups (optionally having 1-3 substituting moieties β on the arylmoiety) are preferable, further phenylaminocarbonyl groups (optionallyhaving 1-3 substituting moieties β on the phenyl moiety) are morepreferable, and phenylaminocarbonyl groups (optionally having onesubstituting moiety on the phenyl moiety) are the most preferable. WhenX and α₁ represent an “amino group optionally having 1 or 2 substitutingmoieties β”, examples of said group are amino, methylamino, ethylamino,propylamino, isopropylamino, butylamino, s-butylamino, t-butylamino,pentylamino, hexylamino, dimethylamino, diethylamino,N-ethyl-N-methylamino, dipropylamino, dibutylamino, dipentylamino,dihexylamino, phenylamino, 1- or 2-indenylamino, 1- or 2-naphthylamino,benzylamino, 1- or 2-naphthylmethylamino, 1-indenylmethylamino, 1- or2-phenethylamino, 1-, 2- or 3-phenylpropylamino, 4-phenylbutylamino,1-phenylbutylamino, 5-phenylpentylamino, 6-phenylhexylamino,dibenzylamino, formylamino, acetylamino, propionylamino, butyrylamino,isobutyrylamino, valerylamino, isovalerylamino, pivaloylamino,hexanoylamino, acryloylamino, methacryloylamino, crotonoylamino,benzoylamino, 1-indanecarbonylamino, 1- or 2-naphthoylamino,1-indanecarbonylamino, 1- or 2-naphthoylamino, phenylacetylamino,3-phenylpropionylamino, 4-phenylbutyrylamino, 5-phenylpentanoylamino,6-phenylhexanoylamino, cyclopropionylamino, cyclobutyrylamino,cyclopentanoylamino, cyclohexanoylamino, pyrrolylcarbonylamino,imidazolylcarbonylamino, pyrazolylcarbonylamino, triazolylcarbonylamino,tetrazolylcarbonylamino, nicotinoylamino, isonicotinoylamino,pyrazinylcarbonylamino, pyrimidinylcarbonylamino,pyridazinylcarbonylamino, thiazolylcarbonylamino, oxazolylcarbonylamino,oxadiazolylcarbonylamino, thiadiazolylcarbonylamino, N,N-diacetylamino,N-formyl-N-hexylamino, N-acetyl-N-methylamino, N-acetyl-N-ethylamino,N-acetyl-N-propylamino, N-acetyl-N-butylamino, N-acetyl-N-pentylamino,N-acetyl-N-hexylamino, N-benzoyl-N-methylamino, N-benzoyl-N-ethylamino,N-benzoyl-N-propylamino, N-benzoyl-N-butylamino,N-benzoyl-N-pentylamino, N-benzoyl-N-hexylamino,N-benzoyl-N-phenylamino, N-benzyl-N-benzoylamino,N-hexyl-N-1-naphthoylamino, N-hexyl-N-2-naphthoylamino,N-hexyl-N-phenylacetylamino, N-isobutyl-N-cycloheptanoylamino,N-butyl-N-nicotinoylamino, N-hexyl-N-nicotinoylamino,N-isonicotinoyl-N-hexylamino and 4-trifluoromethylphenylcarbamoylamino.As said group, amino groups optionally having 1 or 2 substitutingmoieties selected from C₁-C₁₀ alkyl, C₁-C₇ aliphatic acyl andphenylaminocarbonyl group (optionally having 1-3 substituting moieties γon the phenyl moiety) are preferable, further amino groups optionallyhaving 1 or 2 substituting moieties selected from C₁-C₆ alkyl, C₁-C₂aliphatic acyl and phenylaminocarbonyl group (optionally having onesubstituting moiety γ on the phenyl moiety) are more preferable, andfurthermore amino groups optionally substituted with onephenylaminocarbonyl groups (optionally having one substituting moiety γon the phenyl moiety) are the most preferable.

[0106] When R₁, R₂, R₃, R₄, Z₁, Z₃ and Z₄ represent a “C₆-C₁₀ aryl group(optionally having 1-5 substituting moieties α₁)”, in view of thedefinition of X, α₁ and α₂ described above, examples of said grouphaving such a substituting moiety are methylphenyl,trifluoromethylphenyl, hydroxyphenyl, 4-hydroxy-2,3,5-trimethylphenyl,3,5-di-t-butyl-4-hydroxyphenyl, adamantylphenyl,4-amino-3,5-dimethylphenyl, acetylphenyl, methoxyphenyl, benzoylphenyl,fluorophenyl, difluorophenyl, chlorophenyl, dichlorophenyl, bromophenyl,nitrophenyl, (dimethylamino)phenyl, biphenylyl, methylbiphenylyl,methylnaphthyl, trifluoronaphthyl, hydroxynaphthyl, methoxynaphthyl,fluoronaphthyl and chloronaphthyl. As to said group, C₆-C₁₀ aryl groups(optionally having 1-3 substituting moieties α₁) are preferable, furtherphenyl groups (optionally having 1-3 substituting moieties α₁) are morepreferable, furthermore phenyl groups (optionally having 1 or 2substituting moieties α₁) are yet more preferable, and phenyl groups(optionally having one substituting moiety α₁) are the most preferable.

[0107] When Z₂ represents a “C₆-C₁₀ aryl group (optionally having 1-5substituting moieties α₁)”, examples of said group are adamantylphenyl,biphenylyl, methylbiphenylyl, benzylphenyl, acetylphenyl,cyclohexylcarbonylphenyl, benzoylphenyl, benzylcarbonylphenyl,pyridinecarbonylphenyl and phenylaminocarbonyl. As to said group, C₆-C₁₀aryl groups (optionally having 1-3 substituting moieties α₂) arepreferable, further phenyl groups (optionally having 1-3 substitutingmoieties α₂) are more preferable, furthermore phenyl groups (optionallyhaving 1 or 2 substituting moiety α₂) are yet more preferable, andphenyl groups (optionally having one substituting moiety α₂) are themost preferable.

[0108] When R₁, R₂, R₃, R₄, Z₁, Z₃ and Z₄ represents a “C₇-C₁₆ aralkylgroup (optionally having 1-5 substituting moieties α₁ on the aryl moietythereof)”, examples of said group having such a substituting moiety aremethylbenzyl, trifluoromethylbenzyl, hydroxybenzyl,4-hydroxy-2,3,5-trimethylbenzyl, 3,5-di-t-butyl-4-hydroxybenzyl,adamantylbenzyl, 4-amino-3,5-dimethylbenzyl, acetylbenzyl,methoxybenzyl, benzoylbenzyl, fluorobenzyl, difluorobenzyl,chlorobenzyl, dichlorobenzyl, nitrobenzyl, (dimethylamino)benzyl,biphenylylmethyl, methylbiphenylylmethyl, methylphenethyl,trifluoromethylphenethyl, hydroxyphenethyl,4-hydroxy-2,3,5-trimethylphenethyl, 3,5-di-t-butyl-4-hydroxyphenethyl,adamantylphenethyl, 4-amino-3,5-dimethylphenethyl, acetylphenethyl,methoxyphenethyl, benzoylphenethyl, fluorophenethyl, difluorophenethyl,chlorophenethyl, nitrophenethyl, (dimethylamino)phenethyl,biphenylylethyl, methylbiphenylyl, methylphenylbutyl,trifluoromethylphenylbutyl, hydroxyphenylbutyl,4-hydroxy-2,3,5-trimethylphenylbutyl,3,5-di-t-butyl-4-hydroxyphenylbutyl, adamantylphenylbutyl,4-amino-3,5-dimethylphenylbutyl, acetylphenylbutyl, methoxyphenylbutyl,fluorophenylbutyl, chiorophenylbutyl, nitrophenylbutyl,(dimethyl)phenylbutyl, biphenylylbutyl, methylnaphthylmethyl,trifluoronaphthylmethyl, hydroxynaphthylmethyl, methoxynaphthylmethyl,fluoronaphthylmethyl and chloropnaphthylmethyl. As to said group, C₇-C₁₆aralkyl groups (optionally having 1-3 substituting moieties α₁ on thearyl moiety) are preferable, further phenyl-C₁-C₆ alkyl groups(optionally having 1-3 substituting moieties α₁ on the phenyl moiety)are more preferable, further phenyl-C₁-C6 alkyl groups (optionallyhaving one substituting moiety α₁ on the phenyl moiety) are yet morepreferable, phenyl-C₁-C₄ alkyl groups (optionally having onesubstituting moiety α₁ on the phenyl moiety) are still furtherpreferable, and further phenyl-C₁-C₂ alkyl groups (optionally having onesubstituting moiety α₁ on the phenyl moiety) are the most preferable.

[0109] When R₁, R₂ and R₃ represent a “C₆-C₁₀ arylsulfonyl group(optionally having 1-5 substituting moieties α₁)”, examples of saidgroup having such a substituting moiety are methylphenylsulfonyl,acetylphenylsulfonyl, benzoylphenylsulfonyl, biphenylylsulfonyl,methylbiphenylylsulfonyl, methylnaphthylsulfonyl, acetylnaphthylsulfonyland benzoylnaphthylsulfonyl. As to said group, C₆-C₁₀ arylsulfonylgroups (optionally having 1-3 substituting moieties α₁) are preferable,further phenylsulfonyl groups (optionally having 1-3 substitutingmoieties α₁) are more preferable, and furthermore phenylsulfonyl groups(optionally having one substituting moiety α₁) are the most preferable.

[0110] When R₁, R₂ and R₃ represent a “C₇-C₁₆ aralkylsulfonyl group(optionally having 1-5 substituting moieties α₁ on the aryl moietythereof)”, examples of said group having such a substituting moiety aremethylbenzylsulfonyl, acetylbenzylsulfonyl, benzoylbenzylsulfonyl,biphenylylmethylsulfonyl, methylbiphenylylmethylsulfonyl,methylnaphthylmethylsulfonyl, acetylnaphthylmethylsulfonyl,benzoylnaphthylmethylsulfonyl, methylphenethylsulfonyl,acetylphenethylsulfonyl, methylnaphthylethylsulfonyl,acetylnaphthylethylsulfonyl, methylphenylbutylsulfonyl,acetylphenylbutylsulfonyl, methylnaphthylbutylsulfonyl andacetylnaphthylbutylsulfonyl. As to said group, C₇-C₁₆ aralkylsulfonylgroups (optionally having 1-3 substituting moieties α₁ on the arylmoiety) are preferable, further phenyl-C₁-C₆ alkylsulfonyl groups(optionally having 1-3 substituting moieties α₁ on the phenyl moiety)are more preferable, furthermore phenyl-C₁-C₄ alkylsulfonyl groups(optionally having one substituting moiety α₁ on the phenyl moiety) areyet more preferable, and benzylsulfonyl or phenethylsulfonyl groups(optionally having one substituting moiety α on the phenyl moiety) arethe most preferable.

[0111] When Z₁ and Z₄ represent a “C₆-C₁₀ aryloxy groups (optionallyhaving 1-5 substituting moieties α₁)”, examples of said group havingsuch a substituting moiety are methylphenoxy, trifluoromethylphenoxy,hydroxyphenoxy, 4-hydroxy-2,3,5-trimethylphenoxy,3,5-di-t-butyl-4-hydroxyphenoxy, cyclopropylphenoxy, adamantylphenoxy,cyanophenoxy, nitrophenoxy, 4-amino-3,5-dimethylphenoxy, acetylphenoxy,methoxyphenoxy, benzoylphenoxy, fluorophenoxy, difluorophenoxy,chlorophenoxy, dichlorophenoxy, nitrophenoxy, (dimethylamino)phenoxy,4-(4-trifluoromethylphenylcarbamoylamino)-3,5-dimethylphenoxy,biphenylyloxy, methylbiphenylyloxy, dimethylaminophenoxy,methylnaphthyloxy, trifluoronaphthyloxy, hydroxynaphthyloxy,methoxynaphthyloxy, fluoronaphthyloxy and chloronaphthyloxy. As to saidgroup, C₆-C₁₀ aryloxy groups (optionally having 1-3 substitutingmoieties α₁) are preferable, further phenoxy groups (optionally having1-5 substituting moieties α₁) are more preferable, furthermore phenoxygroups (optionally having one or two substituting moieties α₁) are yetmore preferable, and phenoxy groups (optionally having one substitutingmoiety α₁) are the most preferable.

[0112] When Z₁ and Z₄ represent a “C₇-C₁₆ aralkyloxy group (optionallyhaving 1-5 substituting moieties α₁ hereafter described on the arylmoiety thereof)”, examples of said group having such a substitutingmoiety are methylbenzyloxy, trifluoromethylbenzyloxy, hydroxybenzyloxy,4-hydroxy-2,3,5-trimethylbenzyloxy, 3,5-di-t-butyl-4-hydroxybenzyloxy,adamantylbenzyloxy, 4-amino-3,5-dimethylbenzyloxy, acetylbenzyloxy,methoxybenzyloxy, benzoylbenzyloxy, fluorobenzyloxy, difluorobenzyloxy,chlorobenzyloxy, dichlorobenzyloxy, nitrobenzyloxy,(dimethylamino)benzyloxy, biphenylylmethoxy, methylbiphenylylmethoxy,methylphenethyloxy, trifluoromethylphenethyloxy, hydroxyphenethyloxy,4-hydroxy-2,3,5-trimethylphenethyloxy,3,5-di-t-butyl-4-hydroxyphenethyloxy, adamantylphenethyloxy,4-amino-3,5-dimethylphenethyloxy, acetylphenethyloxy,methoxyphenethyloxy, benzoylphenethyloxy, fluorophenethyloxy,difluorophenethyloxy, chlorophenethyloxy, nitrophenethyloxy,(dimethylamino)phenethyloxy, biphenylylethyloxy, methylbiphenylylethoxy,methylphenylbutoxy, trifluoromethylphenylbutoxy, hydroxyphenylbutoxy,4-hydroxy-2,3,5-trimethylphenylbutoxy,3,5-di-t-butyl-4-hydroxyphenylbutoxy, adamantylphenylbutoxy,4-amino-3,5-dimethylphenylbutoxy, acetylphenylbutoxy,methoxyphenylbutoxy, fluorophenylbutoxy, chlorophenylbutoxy,nitrophenylbutoxy, (dimethylamino)phenylbutoxy, biphenylbutoxy,methylnaphthylmethoxy, trifluoronaphthylmethoxy, hydroxynaphthylmethoxy,methoxynaphthylmethoxy, fluoronaphthylmethoxy and chloronaphthylmethoxy.As to said group, C₇-C₁₆ aralkyloxy groups (optionally having 1-3substituting moieties α₁ on the aryl moiety thereof) are preferable,further phenyl-C₁-C₆ alkyloxy groups (optionally having 1-3 substitutingmoieties α₁ on the phenyl moiety) are more preferable, furthermorephenyl-C₁-C₆ alkyloxy groups (optionally having one substituting moietyα₁ on the phenyl moiety) are yet more preferable, moreover phenyl-C₁-C₄alkyloxy groups (optionally having one substituting moiety α₁ on thephenyl moiety) are still more preferable, and phenyl-C₁-C₂ alkyloxygroups (optionally having one substituting moiety α₁ on the phenylmoiety) are the most preferable.

[0113] When Z₁ and Z₄ represent a “saturated heterocyclic ring-oxy group(optionally having 1-5 substituting moieties α₁)”, said group means amonovalent group mainly derived from a monosaccharide. Saidmonosaccharides illustratively include pentoses such as arabinose,xylose, ribose, etc., hexoses such as glucose, galactose, mannose, etc.,aminosugars such as glucosamine, galactosamine, etc., uronic acids suchas glucuronic acid, etc. As to said groups, monovalent groups derivedfrom monosaccharides showing physiological activity in vivo ofwarm-blooded animals (particularly human beings) are preferable, furthermonovalent groups derived from an uronic acid are more preferable, andmonovalent groups derived from glucuronic acid are particularlypreferable.

[0114] When Z₂ and Z₃ represent a “saturated heterocyclic ring group(optionally having 1-5 substituting moieties α₁)”, said group means amonovalent group mainly derived by removing the hydroxy group from saidmonosaccharide. As to said group, monovalent groups derived frommonosaccharides showing phyiological activity in vivo of warm-bloodedanimals (particularly human beings) are preferable, further monovalentgroups derived from an uronic acid are more preferable, and monovalentgroups derived from glucuronic acid are particularly preferable.

[0115] When Z₁ and Z₄ represent a “monocyclic type heteroaromaticring-oxy group (optionally having 1-5 substituting moieties α₁)”,examples of said group are fluorofuryloxy, fluorothienyloxy,fluoropyrrolyloxy, fluorooxazolyloxy, fluorothiazolyloxy,fluorotriazolyloxy, fluoropyranyloxy, fluoropyridyloxy,fluoropyridazinyloxy, fluoropyrimidinyloxy, methylfuryloxy,methylthienyloxy, methylpyrrolyloxy, methyloxazolyloxy,methylthiazolyloxy, methylpyridyloxy, methoxyfuryl, methoxythienyl,methoxypyrrolyloxy, methoxyoxazolyloxy, methylthiazolyloxy,methoxypyridyloxy, dimethylaminofuryloxy, dimethylaminoethienyloxy,dimethylaminopyrrolyloxy, dimethylaminooxazolyloxy,dimethylaminothiazolyloxy, and dimethylaminopyridyloxy. As to saidgroup, monocyclic type heteroaromatic ring-oxy groups (optionally having1-3 substituting moieties α₁) are preferable, further 5- or 6-membermonocyclic type heteroaromatic ring-oxy groups (optionally having one ortwo substituting moieties α₁) are more preferable, furthermore 5- or6-member monocyclic type heteroaromatic ring-oxy groups (optionallyhaving one or two substituting moieties α₁) are yet more preferable, and5- or 6-member monocyclic type heteroaromatic ring-oxy groups containingone or more hetero-atom(s) (optionally having one substituting moietyα₁) are the most preferable.

[0116] When Z₁ and Z₄ represent a “C₆-C₁₀ arylthio group (optionallyhaving 1-5 substituting moieties α₁)”, examples of said group aremethylphenylthio, trifluoromethylphenylthio, hydroxyphenylthio,4-hydroxy-2,3,5-trimethylphenylthio, 3,5-di-t-butyl-4-hydroxyphenylthio,adamantylphenylthio, 4-amino-3,5-dimethylphenylthio, acetylphenylthio,methoxyphenylthio, benzoylphenylthio, fluorophenylthio,difluorophenylthio, chlorophenylthio, dichlorophenylthio,nitrophenylthio, (dimethylamino)phenylthio, biphenylylthio,methylbiphenylylthio, methylnaphthylthio, trifluoronaphthylthio,hydroxynaphthylthio, methoxynaphthylthio, fluoronaphthylthio, andchloronaphthylthio. As to said group, C₆-C₁₀ arylthio groups (optionallyhaving 1-3 substituting moieties α₁) are preferable, further phenylthiogroups (optionally having 1-3 substituting moieties α₁) are morepreferable, furthermore phenylthio groups (optionally having one or twosubstituting moieties α₁) are yet more preferable, and phenylthio groups(optionally having one substituting moiety α₁) are the most preferable.

[0117] When Z₁ and Z₄ represent a “C₇-C₁₆ aralkylthio group (optionallyhaving 1-5 substituting moieties α₁ on the aryl moiety thereof)”,examples of said group having such a substituting moiety aremethylbenzylthio, trifluoromethylbenzylthio, hydroxybenzylthio,4-hydroxy-2,3,5-trimethylbenzylthio, 3,5-di-t-butyl-4-hydroxybenzylthio,adamantylbenzylthio, 4-amino-3,5-dimethylbenzylthio, acetylbenzylthio,methoxybenzylthio, benzoylbenzylthio, fluorobenzylthio,difluorobenzylthio, chlorobenzylthio, dichlorobenzylthio,nitrobenzylthio, (dimethylamino)benzylthio, biphenylylmethylthio,methylbiphenylylmethylthio, methylphenethylthio,trifluoromethylphenethylthio, hydroxyphenethylthio,4-hydroxy-2,3,5-trifluoro-phenethylthio, 3,5-di-t-butyl4hydroxyphenethylthio, adamantylphenethylthio,4-amino-3,5-dimethylphenethylthio, acetylphenethylthio,methoxyphenethylthio, benzoylphenethylthio, fluorophenethylthio,difluorophenethylthio, chlorophenethylthio, nitrophenethylthio,(dimethylamino)phenethylthio, biphenylylethylthio,methylbiphenylylethylthio, methylphenylylbutylthio,trifluoromethylphenylbutylthio, hydroxyphenylbutylthio,4-hydroxy-2,3,5-trimethylphenylbutylthio,3,5-di-t-butyl-4-hydroxyphenylbutylthio, adamantyl-phenylbutylthio,4-amino-3,5-dimethylphenylbutylthio, acetylphenylbutylthio,methoxyphenylbutylthio, fluorophenylbutylthio, chlorophenylbutylthio,nitrophenylbutylthio, (dimethylamino)phenylbutylthio,biphenylylbutylthio, methylnaphthylmethylthio,trifluoromethylnaphthylmethylthio, hydroxynaphthylmethylthio,methoxynaphthylmethylthio, fluoronaphthylmethylthio, andchloronaphthylmethylthio. As to said groups, C₇-C₁₆ aralkylthio groups(optionally having 1-3 substituting moieties α₁ on the aryl moiety) arepreferable, further phenyl-C₁-C₆ alkylthio groups (optionally having 1-3substituting moieties α₁ on the phenyl moiety) are more preferable,furthermore phenyl-C₁-C₆ alkylthio groups (optionally having onesubstituting moiety α₁ on the phenyl moiety) are yet more preferable,then phenyl-C₁-C₄ alkylthio groups (optionally having one substitutingmoiety α₁ on the phenyl moiety) are still more preferable, andphenyl-C₁-C₂ alkylthio groups (optionally having one substituting moietyα₁ on the phenyl moiety) are the most preferable.

[0118] When Z₁ and Z₄ represent a “saturated heterocyclic ring-thiogroup (optionally having 1-5 substituting moieties α₁)”, examples ofsaid group having such a substituting moiety are methylpyrrolidylthio,methoxypyrrolidylthio, methyltetrahydrofuranylthio,methoxytetrahydrofuranylthio, methylpiperidylthio, methoxypiperidylthio,methyltetrahydropyranylthio, methoxytetrahydropyranylthio,methyltetrahydrothiopyranylthio, methoxytetrahydrothiopyranylthio,methylpiperazinylthio, methoxypiperazinylthio, methylmorpholylthio,methoxymorpholylthio, methylthiomorpholylthio andmethoxythiomorpholylthio. As to said group, 5- or 6-member saturatedheterocyclic ring-thio groups (optionally having 1-5 substitutingmoieties α₁) are preferable, further 5- or 6-member saturatedheterocyclic ring-thio groups (optionally having 1-3 substitutingmoieties α₁) are more preferable, and furthermore 5- or 6-membersaturated heterocyclic ring-thio groups (optionally having onesubstituting moiety α₁) are the most preferable.

[0119] When Z₁ and Z₄ represent a “monocyclic type heteroaromaticring-thio group (optionally having 1-5 substituting moieties α₁)”,examples of said group having the substituting moiety arefluorofurylthio, fluorothienylthio, fluoropyrrolylthio,fluorooxazolylthio, fluorothiazolylthio, fluorotriazolylthio,fluoropyranylthio, fluoropyridylthio, fluoropyridazinylthio,fluoropyrimidinylthio, methylfurylthio, methylthienylthio,methylpyrrolylthio, methyloxazolylthio, methylthiazolylthio,methylpyridylthio, methoxyfurylthio, methoxythienylthio,methoxypyrrolylthio, methoxyoxazolylthio, methoxythiazolylthio,methoxypyridylthio, dimethylaminofurylthio, dimethylaminothienylthio,dimethylaminopyrrolylthio, dimethylaminooxazolylthio,dimethylaminothiazolylthio and dimethylaminopyridylthio. As to saidgroup, 5-7 member monocyclic type heteroaromatic ring-thio groups(optionally having 1-3 subsituting moieties α₁) are preferable, further5-6 member monocyclic type heteroaromatic ring-thio groups (optionallyhaving one or two substituting moieties α₁) are more preferable,furthermore 5 or 6-member monocyclic type heteroaromatic ring-thiogroups (optionally having one substituting moiety α₁) are yet morepreferable, and 5- or 6-member monocyclic type heteroaromatic ring-thiogroups containing one or two heteroatom(s) (optionally having onesubstituting moiety α₁) are the most preferable.

[0120] When Z₁ and Z₄ represent an “amino group (optionally having 1 or2 substituting moieties α₁)”, examples of said group are amino,methylamino, ethylamino, propylamino, isopropylamino, butylamino,s-butylamino, t-butylamino, pentylamino, hexylamino, dimethylamino,diethylamino, N-ethyl-N-methylamino, dipropylamino, dibutylamino,dipentylamino, dihexylamino, phenylamino, 1 - or 2-indenylamino, 1- or2-naphthylamino, diphenylamino, formylamino, acetylamino,propionylamino, butyrylamino, isobutyrylamino, valerylamino,isovalerylamino, pivaloylamino, hexanoylamino, acryloylamino,methacryloylamino, crotonoylamino, benzoylamino, 1-indanecarbonylamino,1- or 2-naphthoylamino, 2,6-diisopropylbenzoylamino, phenylacetylamino,3-phenyl-propionylamino, 4-phenylbutyrylamino, 5-phenylpentanoylamino,6-phenylhexanoylamino, cyclopropanecarbonylamino,cyclobutanecarbonylamino, cyclopentanecarbonylamino, cyclohexanoylamino,pyrrolylcarbonylamino, imidazolylcarbonylamino, pyrazolylcarbonylamino,triazolylcarbonylamino, tetrazolylcarbonylamino, nicotinoylamino,isonicotinoylamino, pyrazinylcarbonyl-amino, pyrimidinylcarbonylamino,pyridazinylcarbonylamino, thiazolylcarbonylamino, oxazolylcarbonylamino,oxadiazolylcarbonylamino, thiadiazolylcarbonylamino,4-trifluoromethylphenylcarbamoylamino, N,N-diacetylamino,N-formyl-N-hexylamino, N-acetyl-N-methylamino, N-acetyl-N-ethylamino,N-acetyl-N-propylamino, N-acetyl-N-butylamino, N-acetyl-N-pentylamino,N-acetyl-N-hexylamino, N-benzoyl-N-methylamino, N-benzoyl-N-ethylamino,N-benzoyl-N-propylamino, N-benzoyl-N-butylamino,N-benzoyl-N-pentylamino, N-benzoyl-N-hexylamino,N-benzoyl-N-phenylamino, N-benzyl-N-benzoylamino,N-hexyl-N-1-naphthoylamino, N-hexyl-N-2-naphthoylamino,N-hexyl-N-phenylacetylamino, N-isobutyl-N-cycloheptanecarbonylamino,N-butyl-N-nictonoylamino, N-hexyl-N-nicotinoylamino, andN-isonicotinoyl-N-hexylamino. As to said group, amino groups (optionallyhaving one or two substituting moieties selected from C₁-C₆ alkyl, C₁-C₇aliphatic acyl, C₆-C₁₀ aryl optionally having 1-3 substituting moietiesβ, C₇-C₁₆ aralkyl optionally having 1-3 substituting moieties on thearyl moiety thereof and C₇-C₁₁ arylcarbonyl optionally having 1-3substituting moieties β on the aryl moiety thereof) are preferable, andfurther amino groups (optionally having one or two substituting moietiesβ selected from C₁-C₄ alkyl, C₁-C₂ aliphatic acyl, phenyl optionallyhaving one substituting moiety β, phenyl-C₁-C₄ alkyl optionally havingone substituting moiety β on the phenyl moiety thereof and benzoyloptionally having one substituting moiety β on the phenyl moietythereof) are more preferable.

[0121] The α-substituted carboxylic acid derivatives of the compounds(I) to (IV) in the present invention having a carboxyl group can beconverted into their salts in a conventional manner. Examples of suchsalts are alkali metal salts such as the sodium salt, potassium salt orlithium salt; alkaline earth metal salts such as the calcium salt ormagnesium salt; metal salts such as the aluminum salt, iron salt, zincsalt, copper salt, nickel salt, cobalt salt, etc.; inorganic salts suchas the ammonium salt; amine salts like organic salts such as thet-octylamine salt, dibenzylamine salt, morpholine salt, glucosaminesalt, phenylglycine alkyl ester salt, ethylenediamine salt,N-methylglucamine salt, guanidine salt, diethylamine salt, triethylaminesalt, dicyclohexylamine salt, N,N′-dibenzylethylenediamine salt,chloroprocaine salt, procaine salt, diethanolamine salt;N-benzyl-N-phenethylamine salt, piperazine salt or tetramethylammoniumsalt; and tris(hydroxymethyl)aminomethane salt.

[0122] The α-substituted carboxylic acid derivatives of the compounds(I) to (IV) in the present invention can be converted into their saltseven in the case of their having any basic moiety such as a pyridyl orquinolyl group and also in the case of having no bases. Examples of suchsalts are hydrohalogenic acid salts such as hydrofluoride,hydrochloride, hydrobromide, hydroiodide; inorganic acid salts such asnitrate, perchlorate, sulfate, phosphate; lower alkanesulfonic acidsalts such as methanesulfonate, trifluoromethanesulfonate,ethanesulfonate; arylsulfonic acid salts such as benzenesulfonate,p-toluenesulfonate, etc.; amino acid salts such as glutamate, aspartate,etc.; organic carboxylic acid salts such as fumarate, succinate,citrate, tartrate, oxalate, maleate; amino acid salts such as ornithine,glutamate, aspartate and the like. Of these, hydrohalogenic acid saltsand organic acid salts are preferable. The α-substituted carboxylic acidderivatives of the compounds (I) to (IV) in the present invention can beconverted into their pharmacologically acceptable esters in aconventional manner. No special limitation is given to thesepharmacologically acceptable esters of the α-substituted carboxylic acidderivatives of the compounds (I) to (IV) as long as they are medicallyuseful and pharmacologically acceptable in the form of the α-substitutedcarboxylic acid derivatives of the compounds (I) to (IV). The esters ofthe α-substituted carboxylic acid derivatives of the compounds (I) to(IV) in the present invention illustratively include C₁-C₆ alkylsubstituted by C₁-C₆ alkyl, C₇-C₁₉ aralkyl or C₁-C₇ aliphatic acyloxy,C₁-C₆ alkyl substituted by C₁-C₇ alkyloxycarbonyloxy, C₁-C₆ alkylsubstituted by C₅-C₇ cycloalkylcarbonyloxy, C₁-C₆ alkyl substituted byC₆-C₈ cycloalkyloxycarbonyloxy, C₁-C₆ alkyl substituted by C₇-C₁₁arylcarbonyloxy, C₁-C₆ alkyl substituted by C₇-C₁₁ aryloxycarbonyloxyand 2-oxo-1,3-dioxolene-4-ylmethyl group having C₁-C₆ alkyl as asubstituent at the 5-position.

[0123] Concerning the ester group, C₁-C₆ alkyl groups includeillustratively methyl, ethyl, propyl, isopropyl, butyl, isobutyl,s-butyl, t-butyl, pentyl, methylbutyl, dimethylpropyl, ethylpropyl,hexyl, methylpentyl, dimethylbutyl, ethylbutyl, and trimethylpropyl.C₁-C₄ alkyl groups are preferable, further methyl, ethyl, propyl,isopropyl, butyl or isobutyl are more preferable, and methyl or ethylare the most preferable.

[0124] C₇-C₁₉ aralkyl groups includes benzyl, phenethyl, phenylpropyl,phenylbutyl, naphthylmethyl and benzyl. Benzyl is preferable.

[0125] C₅-C₇ cycloalkyl groups includes cyclopentyl, cyclohexyl andcycloheptyl. Cyclohexyl is preferable.

[0126] C₆-C₁₀ aryl groups includes phenyl and naphthyl, and phenyl ispreferable.

[0127] Preferable examples of the ester residue are methyl, ethyl,propyl, isopropyl, butyl, isobutyl, t-butyl, benzyl, acetoxymethyl,1-(acetoxy)ethyl, propionyloxymethyl, 1-propionyloxyethyl,butyryloxymethyl, 1-butyryloxyethyl, 1-isobutyryloxyethyl,valeryloxymethyl, 1-valeryloxyethyl, isovaleryloxymethyl,1-isovaleryloxyethyl, pivaloyloxymethyl, 1-pivaloyloxyethyl,methoxycarbonyloxymethyl, 1-methoxycarbonyloxyethyl,ethoxycarbonyloxymethyl, 1-ethoxycarbonyloxyethyl,propoxycarbonyloxymethyl, 1-propoxycarbonyloxyethyl,isopropoxycarbonyloxymethyl, 1-isopropoxycarbonyloxyethyl,butoxycarbonyloxymethyl, 1-butoxycarbonyloxyethyl,isobutoxycarbonyloxymethyl, 1-isobutoxycarbonyloxyethyl,t-butoxycarbonyloxymethyl, 1-(t-butoxycarbonyloxy)ethyl,cyclopentanecarbonyloxymethyl, 1-cyclopentanecarbonyloxyethyl,cyclopentanecarbonyloxymethyl, 1-cyclopentanecarbonyloxyethyl,cyclohexanecarbonyloxymethyl, 1-cyclohexanecarbonyloxyethyl,cyclopentyloxycarbonyloxymethyl, 1-cyclopentyloxycarbonyloxyethyl,cyclohexyloxycarbonyloxymethyl, 1-cyclohexyloxycarbonyloxyethyl,benzoyloxymethyl, 1-benzoyloxyethyl, phenoxycarbonyloxymethyl,1-phenoxycarbonyloxyethyl and 5-methyl-2-oxo-1,3-dioxolene-4-ylmethyl.

[0128] The amides of the α-substituted carboxylic acid derivatives ofthe compounds (I) to (IV) in the present invention mean the compounds inwhich the carboxyl group of the α-substituted carboxylic acidderivatives and ammonia are condensed with dehydration. Concretely, theyare prepared by converting the carboxyl group into a —CONH₂ group.

[0129] The compounds of the present invention involve various isomers.For example, the carbon atom at the 2-position of the α-substitutedcarboxylic acid derivatives of the compounds (I) to (IV) isasymmetrical, and any asymmetric carbon exists on the substituent. So,optical isomers may exist in the compounds of the invention.

[0130] Thus, the α-carbon atom is an asymmetric carbon to which R₂, Yand the nitrogen atom are bonded, as a result of which stereoisomers inR conformation and S conformation exist. The present invention involveseach isomer or a mixture of isomers in free ratio. Such stereoisomerscan be prepared by synthesizing α-substituted carboxylic acidderivatives (I)-(IV) from optically resolved starting compounds or bysubjecting once synthesized α-substituted carboxylic acid derivatives(I)-(IV), if desired, to optical resolution by conventional opticalresolution methods or separating methods, or by asymmetric synthesis.

[0131] Further, when Y represents a sulfoxide group, the sulfur atombecomes an asymmetric center to afford optical isomers. Also in thiscase, the respective isomers or a mixture in a free ratio are includedin the scope of the present invention, and such stereoisomers can beoptically resolved by conventional optical resolution methods orseparating methods, or they can be also prepared by asymmetricsynthesis. Further, geometric isomers can exist also in the cases ofthose compounds having any double bond(s).

[0132] The present invention includes all these kinds of isomers.

[0133] In addition, the compounds (I) to (IV) in the present inventionmay absorb water, be attached to adsorbed water, be converted into ahydrate or form a solvate by allowing to leave in the atmosphere or bybeing recrystallized. They are to be included in the present invention.

[0134] Furthermore, compounds (I)-(IV) of the present invention mayabsorb another kind of solvent to give a solvate, which will be includedin the present invention. Moreover, compounds which may be converted invivo by metabolism into the α-substituted carboxylic acid derivatives(I)-(IV) or pharmacologically acceptable salts thereof of the presentinvention, namely so-called pro-drugs are included also in thisinvention.

[0135] Further, a pharmaceutical composition may be prepared by admixingone of sulfonylureas, α-glucosidase inhibitors, aldose reductaseinhibitors, biguanides, statin type compounds, squalene synthesisinhibitors, fibrate type compounds, LDL disassimilation promotors,angiotensin II antagonists, angiotensin converting enzyme inhibitors,anti-cancer agents, and RXR activators together with said α-substitutedcarboxylic acid derivatives (I)-(IV), their pharmacologically acceptableesters, their pharmacologically acceptable amides and theirpharmacologically acceptable salts. The sulfonylureas in theabove-described definition mean a drug capable of accelerating insulinexcretion and illustratively include tolbutamide, acetohexamide,tolazamide, chlorpropamide, etc.

[0136] The α-glucosidase inhibitors above-described mean a drug capableof inhibiting digestive enzymes such as amylase, maltase, α-dextrinase,sucrase, etc. so as to delay the digestion of starch and sucrose, andillustratively include acarbose, N-(1,3-dihydroxy-2-propyl)valiolamine(international non-proprietary name: voglibose), miglitol, and so on.

[0137] The aldose reductase inhibitors in the description above mean adrug capable of inhibiting diabetic complications by inhibiting therate-determining enzyme at the first step of the polyol route andillustratively includes tolrestat, epalrestat, 2,7-difluoro-spiro(9H-fluoren-9,4′-imidazolindin)-2′,5′-dione (internationalnon-proprietary name: imirestat),3-[(4-bromo-2-fluorophenyl)methyl]-7-chloro-3,4-dihydro-2,4-dioxo-1(2H)-quinazolinacetate (international non-proprietary name: zenarestat),6-fluoro-2,3-dihydro-2′,5′-dioxo-spiro[4H-1-benzopyran4,4′-imidazolidin]-2-carboxamide(SNK-860), zopolrestat, sorbinil,1-[(3-bromo-2-benzofuranyl)sulfonyl]-2,4-imidazolidinedione (M-16209),and so on.

[0138] The biguanides in the description above mean a drug havinganaerobic glycolysis promoting activity, peripheral insulin enhancingactivity, glucose intestinal absorption suppression activity, hepaticglucose neogenesis suppression activity, aliphatic acid oxidationinhibition activity, and the like, and illustratively includephenformin, metformin, buformin, etc.

[0139] The statin type compounds in the description above mean a drugcapable of lowering blood cholesterol by inhibitinghydroxymethylglutaryl CoA (HMG-CoA) reductase, and illustrativelyinclude pravastatin and its sodium salt, simvastatin, lovastatin,atorvastatin, celivastatin, fluvastatin, etc.

[0140] The squalene synthesis inhibitors in the description above mean adrug capable of lowering blood cholesterol by inhibiting squalenesynthesis and illustratively include monopotassium(S)-α-[bis(2,2-dimethyl-1-oxopropoxy)methoxy]phosphinyl-3-phenoxybenzene-butanesulfonate(BMS-188494), and so on.

[0141] The fibrate type compounds in the description above mean a drugcapable of lowering blood triglyceride levels by suppressing thesynthesis and excretion of triglycerides in the liver and activatinglipoprotein lipase, and illustratively include bezafibrate,beclofibrate, binifibrate, cyprofibrate, clinofibrate, clofibrate,clofibric acid, etofibrate, fenofibrate, gemfibrozil, nicofibrate,pirifibrate, ronifibrate, simfibrate, thefibrate, etc.

[0142] The LDL disassimilation promotors in the description above mean adrug capable of lowering blood cholesterol by enhancing LDL (low densitylipoprotein) acceptor activity and illustratively include thosecompounds or salts thereof disclosed in JP Unexamined, Pub. H7(1995)-316144 Gazette, concretelyN-[2-[4-bis(4-fluorophenyl)methyl-1-piperazinyl]ethyl]-7,7-diphenyl-2,4,6-heptatrienoicacid amide, and so on.

[0143] The statin type compounds, squalene synthesis inhibitors, fibratetype compounds and LDL disassimilation promotors described above may bereplaced by other drugs having blood cholesterol and triglyceridelowering activity. Examples of such drugs are nicotinic acid derivativessuch as nicomol, niceritrol, etc.; anti-oxidants such as probucol, etc.;and ion exchange resin derivatives such as cholestylamine resin, etc.The angiotensin II antagonists in the description above mean a drugcapable of lowering blood pressure by suppressing strongly hypertensiondue to angiotensin II. Examples of such drugs are losartan potassium,candesartan cilexetil, valsartan, termisartan, ormesartan, etc.

[0144] The angiotensin converting enzyme inhibitors in the descriptionabove mean a drug capable of partially lowering blood sugar in diabeticpatients by lowering blood pressure at a time by inhibitingangiotensin-converting enzyme, and illustratively include captopril,enarapril, alacepril, delapril, ramipril, lisinopril, imidapril,benazepril, ceronapril, cilazapril, enalaprilat, fosinopril, moveltiprl,perindopril, quinapril, spirapril, temocapril, trandolapril, etc.

[0145] Examples of preferable α-substituted carboxylic acid derivativeshaving the general formula (I) will be shown below.

[0146] (1) The α-substituted carboxylic acid derivatives (wherein R₁, R₂and R₃ are the same or different, and each is a (i) hydrogen atom, (ii)C₁-C₆ alkyl group, (iii) C₆-C₁₀ aryl group (optionally having 1-3substituting moieties α₁), (iv) C₇-C₁₆ aralkyl group (optionally having1-3 substituting moieties α₁ on the aryl moiety thereof), (v) C₁-C₄alkylsulfonyl group or (vi) C₁-C₆ halogenoalkylsulfonyl group),pharmacologically acceptable esters thereof, pharmacologicallyacceptable amides thereof or pharmacologically acceptable salts thereof.

[0147] (2) The α-substituted carboxylic acid derivatives (wherein R₁, R₂and R₃ are the same or different, and each is a (i) hydrogen atom, (ii)C₁-C₄ alkyl group, (iii) phenyl group (optionally having onesubstituting moiety α₁), (iv) phenyl-C₁-C₂ alkyl group (optionallyhaving 1-3 substituting moieties α₁ on the phenyl moiety) or (v) C₁-C₂alkylsulfonyl group), pharmacologically acceptable esters thereof,pharmacologically acceptable amides thereof or pharmacologicallyacceptable salts thereof.

[0148] (3) The α-substituted carboxylic acid derivatives (wherein R₁, R₂and R₃ are the same or different, and each is a (i) hydrogen atom, (ii)C₁-C₄ alkyl group or (iii) benzyl group (optionally having onesubstituting moiety α₁ on the phenyl moiety thereof)), pharmacologicallyacceptable esters thereof, pharmacologically acceptable amides thereofor pharmacologically acceptable salts thereof.

[0149] (4) The α-substituted carboxylic acid derivatives (wherein R₁ isa C₁-C₂ alkyl group, R₂ is a hydrogen atom, and R₃ is a C₁-C₄ alkylgroup or phenyl-C₁-C₄ alkyl group (optionally having one substitutingmoiety α₁ on the phenyl moiety thereof)), pharmacologically acceptableesters thereof, pharmacologically acceptable amides thereof orpharmacologically acceptable salts thereof.

[0150] (5) The α-substituted carboxylic acid derivatives (wherein R₁ isa C₁-C₂ alkyl group, R₂ is a hydrogen atom and R₃ is a hydrogen atom),pharmacologically acceptable esters thereof, pharmacologicallyacceptable amides thereof or pharmacologically acceptable salts thereof.

[0151] (6) The α-substituted carboxylic acid derivatives (wherein R₁ isa C₁-C₂ alkyl group, R₂ is a hydrogen atom and R₃ is a phenyl group(optionally having one substituting moiety α₁), pharmacologicallyacceptable esters thereof, pharmacologically acceptable amides thereofor pharmacologically acceptable salts thereof.

[0152] (7) The α-substituted carboxylic acid derivatives (wherein R₁ isa C₁-C₂ alkyl group, R₂ is a hydrogen atom and R₃ is a phenyl group(optionally having one substituting moiety α₁), pharmacologicallyacceptable esters thereof, pharmacologically acceptable amides thereofor pharmacologically acceptable salts thereof.

[0153] (8) The α-substituted carboxylic acid derivatives (wherein R₁ isa C₁-C₂ alkyl group, R₂ is hydrogen atom and R₃ is a C₁-C₂ alkylsulfonylgroup), pharmacologically acceptable esters thereof, pharmacologicallyacceptable amides thereof or pharmacologically acceptable salts thereof.

[0154] (9) The α-substituted carboxylic acid derivatives (wherein A is anitrogen atom), pharmacologically acceptable esters thereof,pharmacologically acceptable amides thereof or pharmacologicallyacceptable salts thereof.

[0155] (10) The α-substituted carboxylic acid derivatives (wherein A isa ═CH-group), pharmacologically acceptable esters thereof,pharmacologically acceptable amides thereof or pharmacologicallyacceptable salts thereof.

[0156] (11) The α-substituted carboxylic acid derivatives (wherein B isan oxygen atom), pharmacologically acceptable esters thereof,pharmacologically acceptable amides thereof or pharmacologicallyacceptable salts thereof.

[0157] (12) The α-substituted carboxylic acid derivatives (wherein B isa sulfur atom), pharmacologically acceptable esters thereof,pharmacologically acceptable amides thereof or pharmacologicallyacceptable salts thereof.

[0158] (13) The α-substituted carboxylic acid derivatives (wherein W₁ isa C₁-C₆ alkylene group), pharmacologically acceptable esters thereof,pharmacologically acceptable amides thereof or pharmacologicallyacceptable salts thereof.

[0159] (14) The α-substituted carboxylic acid derivatives (wherein W₁ isa C₁-C₄ alkylene group), pharmacologically acceptable esters thereof,pharmacologically acceptable amides thereof or pharmacologicallyacceptable salts thereof.

[0160] (15) The α-substituted carboxylic acid derivatives (wherein W₁ isa C₁-C₂ alkylene group), pharmacologically acceptable esters thereof,pharmacologically acceptable amides thereof or pharmacologicallyacceptable salts thereof.

[0161] (16) The α-substituted carboxylic acid derivatives (wherein W₁ isa methylene group), pharmacologically acceptable esters thereof,pharmacologically acceptable amides thereof or pharmacologicallyacceptable salts thereof.

[0162] (17) The α-substituted carboxylic acid derivatives (wherein W₂ isa single bond or a C₁-C₆ alkylene group), pharmacologically acceptableesters thereof, pharmacologically acceptable amides thereof orpharmacologically acceptable salts thereof.

[0163] (18) The α-substituted carboxylic acid derivatives (wherein W₂ isa C₁-C₄ alkylene group), pharmacologically acceptable esters thereof,pharmacologically acceptable amides thereof or pharmacologicallyacceptable salts thereof.

[0164] (19) The α-substituted carboxylic acid derivatives (wherein W₂ isa C₁-C₂ alkylene group), pharmacologically acceptable esters thereof,pharmacologically acceptable amides thereof or pharmacologicallyacceptable salts thereof.

[0165] (20) The α-substituted carboxylic acid derivatives (wherein W₂ isa methylene group), pharmacologically acceptable esters thereof,pharmacologically acceptable amides thereof or pharmacologicallyacceptable salts thereof.

[0166] (21) The α-substituted carboxylic acid derivatives (wherein X isa (i) hydrogen atom, (ii) C₁-C₄ alkyl group, (iii) C₁-C₂ halogenoalkylgroup, (iv) C₁-C₄ alkoxy group, (v) halogen atom, (vi) hydroxy group,(vii) cyano group, (viii) nitro group, (ix) C₁-C₅ aliphatic acyl groupor (x) amino group (optionally having one substituting moiety β)),pharmacologically acceptable esters thereof, pharmacologicallyacceptable amides thereof or pharmacologically acceptable salts thereof.

[0167] (22) The α-substituted carboxylic acid derivatives (wherein X is(i) a hydrogen atom, (ii) C₁-C₂ alkyl group, (iii) halogen atom, (iv)hydroxy group, (v) C₁-C₂ aliphatic acyl group or (vi) amino group),pharmacologically acceptable esters thereof, pharmacologicallyacceptable amides thereof or pharmacologically acceptable salts thereof.

[0168] (23) The α-substituted carboxylic acid derivatives (wherein X isa hydrogen atom), pharmacologically acceptable esters thereof,pharmacologically acceptable amides thereof or pharmacologicallyacceptable salts thereof.

[0169] (24) The α-substituted carboxylic acid derivatives (wherein Z₁ isa (i) C₁-C₄ alkoxy group, (ii) C₁-C₄ alkylthio group, (iii) halogenatom, (iv) C₆-C₁₀ aryloxy group (optionally having 1-5 substitutingmoieties α₁), (v) C₇-C₁₆ aralkyloxy group (optionally having 1-3substituting moieties α₁ on the aryl moiety), (vi) C₆-C₁₀ cycloalkyloxygroup, (vii) saturated heterocyclic ring-oxy group (optionally having1-5 substituting moieties α₁), (viii) C₆-C₁₀ arylthio group (optionallyhaving 1-3 substituting moieties α₁), (ix) saturated heterocyclicring-thio group (optionally having 1-5 substituting moieties α₁), (x)amino group (optionally having one substituting moiety α₁) or (xi)hydroxy group), pharmacologically acceptable esters thereof,pharmacologically acceptable amides thereof or pharmacologicallyacceptable salts thereof.

[0170] (25) The α-substituted carboxylic acid derivatives (wherein Z₁ isa (i) C₁-C₂ alkoxy group, (ii) C₁-C₂ alkylthio group, (iii) halogenatom, (iv) phenoxy group (optionally having 1-5 substituting moietiesα₁), (v) saturated heterocyclic ring-oxy group (optionally having 1-5substituting moieties α₁), (vi) phenylthio group (optionally having 1-5substituting moieties α₁), (vii) saturated heterocyclic ring-thio group(optionally having 1-5 substituting moieties α₁), (viii) amino group or(ix) hydroxy group), pharmacologically acceptable esters thereof,pharmacologically acceptable amides thereof or pharmacologicallyacceptable salts thereof.

[0171] (26) The α-substituted carboxylic acid derivatives (wherein Z₁ isa (i) C₁-C₂ alkoxy group, (ii) C₁-C₂ alkylthio group, (iii) phenoxygroup (optionally having 1-5 substituting moieties α₁), (iv) saturatedheterocyclic ring-oxy group (optionally having 1-5 substituting moietiesα₁), (v) phenylthio group (optionally having 1-5 substituting moietiesα₁) or (vi) hydroxy group), pharmacologically acceptable esters thereof,pharmacologically acceptable amides thereof or pharmacologicallyacceptable salts thereof.

[0172] (27) The α-substituted carboxylic acid derivatives (wherein Z₁ isa (i) C₁-C₂ alkoxy group, (ii) phenoxy group (optionally having 1-3substituting moieties α₁) or (iii) phenylthio group (optionally having1-3 substituting moieties α₁), pharmacologically acceptable estersthereof, pharmacologically acceptable amides thereof orpharmacologically acceptable salts thereof.

[0173] (28) The α-substituted carboxylic acid derivatives (wherein thesubstituting moiety α₁ is a (i) C₁-C₆ alkyl group, (ii) C₁-C₂halogenoalkyl group, (iii) C₁-C₄ alkoxy group, (iv) halogen atom, (v)hydroxy group, (vi) cyano group, (vii) nitro group, (viii) C₆-C₁₀cycloalkyl group, (ix) C₁-C₂ aliphatic acyl group, (x) C₇-C₁₁arylcarbonyl group (optionally having 1-3 substituting moieties β), (xi)carbamoyl group, (xii) amino group (optionally having 1 to 2substituting moieties β) or (xiii) carboxyl group), pharmacologicallyacceptable esters thereof, pharmacologically acceptable amides thereofor pharmacologically acceptable salts thereof.

[0174] (29) The α-substituted carboxylic acid derivatives (wherein thesubstituting moiety α₁ is a (i) C₁-C₄ alkyl group, (ii) C₁-C₂halogenoalkyl group, (iii) C₁-C₂ alkoxy group, (iv) halogen atom, (v)hydroxy group, (vi) cyano group, (vii) nitro group, (viii) adamantylgroup, (ix) benzoyl group (optionally having one substituting moiety β),(x) amino group (optionally having one substituting moiety β) or (xi)carboxyl group), pharmacologically acceptable esters thereof,pharmacologically acceptable amides thereof or pharmacologicallyacceptable salts thereof.

[0175] (30) The α-substituted carboxylic acid derivatives (wherein thesubstituting moiety α₁ is a (i) C₁-C₄ alkyl group, (ii) halogen atom,(iii) hydroxy group, (iv) adamantyl group, (v) benzoyl group, (vi) aminogroup (optionally having one substituting moiety β) or (vii) carboxylgroup), pharmacologically acceptable esters thereof, pharmacologicallyacceptable amides thereof or pharmacologically acceptable salts thereof.

[0176] (31) The α-substituted carboxylic acid derivatives (wherein thesubstituting moiety α₁ is a (i) C₁-C₄ alkyl group, (ii) halogen atom,(iii) hydroxy group or (iv) adamantyl group), pharmacologicallyacceptable esters thereof, pharmacologically acceptable amides thereofor pharmacologically acceptable salts thereof.

[0177] (32) The α-substituted carboxylic acid derivatives (wherein thesubstituting moiety α₁ is a C₁-C₄ alkyl group or a hydroxy group),pharmacologically acceptable esters thereof, pharmacologicallyacceptable amides thereof or pharmacologically acceptable salts thereof.

[0178] (33) The α-substituted carboxylic acid derivatives (wherein thesubstituting moiety α₁ is a halogen atom or an adamantyl group),pharmacologically acceptable esters thereof, pharmacologicallyacceptable amides thereof or pharmacologically acceptable salts thereof.

[0179] (34) The α-substituted carboxylic acid derivatives (wherein thesubstituting moiety α₁ is a hydroxy group or a carboxyl group),pharmacologically acceptable esters thereof, pharmacologicallyacceptable amides thereof or pharmacologically acceptable salts thereof.

[0180] (35) The α-substituted carboxylic acid derivatives (wherein thesubstituting moiety α₁ is a C₁-C₄ alkyl group, benzoyl group or aminogroup (optionally having one substituting moiety β)), pharmacologicallyacceptable esters thereof, pharmacologically acceptable amides thereofor pharmacologically acceptable salts thereof.

[0181] (36) The α-substituted carboxylic acid derivatives (wherein thesubstituting moiety α₁ is a benzoyl group), pharmacologically acceptableesters thereof, pharmacologically acceptable amides thereof orpharmacologically acceptable salts thereof.

[0182] (37) The α-substituted carboxylic acid derivatives (wherein thesubstituting moiety β is a (i) C₁-C₆ alkyl group, (ii) halogen atom,(iii) phenyl group (optionally having 1-3 substituting moieties γ), (iv)phenyl-C₁-C₄ alkyl group (optionally having 1-3 substituting moieties γon the phenyl moiety), (v) C₁-C₅ aliphatic acyl group or (vi)phenylaminocarbonyl group (optionally having 1-3 substituting moieties γon the phenyl moiety), pharmacologically acceptable esters thereof,pharmacologically acceptable amides thereof or pharmacologicallyacceptable salts thereof.

[0183] (38) The α-substituted carboxylic acid derivatives (wherein thesubstituting moiety β is a (i) C₁-C₄ alkyl group, (ii) halogen atom or(iii) phenylaminocarbonyl group (optionally having 1-3 substitutingmoieties γ on the phenyl moiety)), pharmacologically acceptable estersthereof, pharmacologically acceptable amides thereof orpharmacologically acceptable salts thereof.

[0184] (39) The α-substituted carboxylic acid derivatives (wherein thesubstituting moiety β is a phenylaminocarbonyl group (optionally havingone substituting moiety γ on the phenyl moiety)), pharmacologicallyacceptable esters thereof, pharmacologically acceptable amides thereofor pharmacologically acceptable salts thereof.

[0185] (40) The α-substituted carboxylic acid derivatives (wherein thesubstituting moiety γ is a (i) C₁-C₂ alkyl group, (ii) C₁-C₂halogenoalkyl group, (iii) halogen atom or (iv) hydroxy group),pharmacologically acceptable esters thereof, pharmacologicallyacceptable amides thereof or pharmacologically acceptable salts thereof.

[0186] (41) The α-substituted carboxylic acid derivatives (wherein thesubstituting moiety γ is a trifluoromethyl group or a halogen atom),pharmacologically acceptable esters thereof, pharmacologicallyacceptable amides thereof or pharmacologically acceptable salts thereof.

[0187] (42) The α-substituted carboxylic acid derivatives (wherein thesubstituting moiety γ is a trifluoromethyl group), pharmacologicallyacceptable esters thereof, pharmacologically acceptable amides thereofor pharmacologically acceptable salts thereof.

[0188] Further, those compounds in which R₁, R₂ and R₃ are selected from(1)-(8) above, A is selected from (9)-(10) above, B is selected from(11)-(12), W₁ is selected from (13)-(16) above, W₂ is selected from(17)-(20) above, X is selected from (21)-(23) above, Z₁ is selected from(24)-(27) above, α₁ is selected from (28)-(36) above, β is selected from(37)-(39) above and γ is selected from (40)-(42) above in theα-substituted carboxylic acid derivatives of the general formula (I) arepreferable.

[0189] For example, the following compounds are preferable in theα-substituted carboxylic acid derivatives of the general formula (I)above.

[0190] (43) The α-substituted carboxylic acid derivatives (wherein R₁,R₂ and R₃ are the same or different, and each is a (i) hydrogen atom,(ii) C₁-C₆ alkyl group, (iii) C₆-C₁₀ aryl group (optionally having 1-3substituting moieties α₁), (iv) C₇-C₁₆ aralkyl group (optionally having1-3 substituting moieties α₁ on the aryl moiety thereof), (v) C₁-C₄alkylsulfonyl group or (vi) C₁-C₆ halogenoalkylsulfonyl group,

[0191] A is a ═CH-group,

[0192] B is an oxygen atom,

[0193] W₁ is a C₁-C₄ alkylene group,

[0194] W₂ is a C₁-C₄ alkylene group,

[0195] X is a (i) hydrogen atom, (ii) C₁-C₄ alkyl group, (iii) C₁-C₂halogenoalkyl group, (iv) C₁-C₄ alkoxy group, (v) halogen atom, (vi)hydroxy group, (vii) cyano group, (viii) nitro group, (ix) C₁-C₅aliphatic acyl group or (x) amino group (optionally having onesubstituting moiety β),

[0196] Y is an oxygen atom or S(O)p (wherein p is an integer from 0 to2),

[0197] Z₁ is a (i) C₁-C₄ alkoxy group, (ii) C₁-C₄ alkylthio group, (iii)halogen atom, (iv) C₆-C₁₀ aryloxy group (optionally having 1-5substituting moieties α₁), (v) C₇-C₁₆ aralkyloxy group (optionallyhaving 1-3 substituting moieties α₁ on the aryl moiety thereof), (vi)C₆-C₁₀ cycloalkyloxy group, (vii) saturated heterocyclic ring-oxy group(optionally having 1-5 substituting moieties α₁), (viii) C₆-C₁₀ arylthiogroup (optionally having 1-5 substituting moieties α₁), (ix) saturatedheterocyclic ring-thio group (optionally having 1-5 substitutingmoieties α₁), (x) amino group (optionally having one substituting moietyα₁ hereafter described) or (xi) hydroxy group, said substituting moietyα₁ is a (i) C₁-C₆ alkyl group, (ii) C₁-C₂ halogenoalkyl group, (iii)C₁-C₄ alkoxy group, (iv) halogen atom, (v) hydroxy group, (vi) cyanogroup, (vii) nitro group, (viii) C₆-C₁₀ cycloalkyl group, (ix) C₁-C₂aliphatic acyl group (x) C₇-C₁₁ arylcarbonyl group (optionally having1-3 substituting moieties γ), (xi) carbamoyl group, (xii) amino group(optionally having 1 to 2 substituting moieties β) or (xiii) carboxylgroup,

[0198] said substituting moiety β is a (i) C₁-C₆ alkyl group, (ii)halogen atom, (iii) phenyl group (optionally having 1-3 substitutingmoieties γ), (iv) phenyl-C ₁-C₄ alkyl group (optionally having 1-3substituting moieties γ on the phenyl moiety thereof), (v) C₁-C₅aliphatic acyl group or (vi) phenylaminocarbonyl group (optionallyhaving 1-3 substituting moieties γ on the phenyl moiety thereof), and

[0199] said substituting moiety γ is a (i) C₁-C₂ alkyl group, (ii) C₁-C₂halogenoalkyl group, (iii) halogen atom or (iv) hydroxy group),pharmacologically acceptable esters thereof, pharmacologicallyacceptable amides thereof or pharmacologically acceptable salts thereof

[0200] (44) The α-substituted carboxylic acid derivatives (wherein R₁,R₂ and R₃ are the same or different, and each is a (i) hydrogen atom,(ii) C₁-C₄ alkyl group, (iii) phenyl group (optionally having onesubstituting moiety α₁), (iv) phenyl-C₁-C₂ alkyl group (optionallyhaving 1-3 substituting moieties α₁ on the phenyl moiety thereof) or (v)C₁-C₂ alkylsulfonyl group,

[0201] A is a ═CH-group,

[0202] B is an oxygen atom,

[0203] W₁ is a C₁-C₂ alkylene group,

[0204] W₂ is a C₁-C₂ alkylene group,

[0205] X is a (i) hydrogen atom, (ii) C₁-C₂ alkyl group, (iii) halogenatom, (iv) hydroxy group, (v) C₁-C₂ aliphatic acyl group or (vi) aminogroup,

[0206] Y is an oxygen atom or S(O)p group (wherein p is an integer of0-2),

[0207] Z₁ is a (i) C₁-C₂ alkoxy group, (ii) C₁-C₂ alkylthio group, (iii)halogen atom, (iv) phenoxy group (optionally having 1-5 substitutingmoieties α₁), (v) saturated heterocyclic ring-oxy group (optionallyhaving 1-5 substituting moieties α₁), (vi) phenylthio group (optionallyhaving 1-5 substituting moieties α₁), (vii) saturated heterocyclicring-thio group (optionally having 1-5 substituting moieties α₁), (viii)amino group or (ix) hydroxy group,

[0208] the substituting moiety α₁ is a (i) C₁-C₄ alkyl group, (ii) C₁-C₂halogenoalkyl group, (iii) C₁-C₂ alkoxy group, (iv) halogen atom, (v)hydroxy group, (vi) cyano group, (vii) nitro group, (viii) adamantylgroup, (ix) benzoyl group (optionally having one substituting moiety β),(x) amino group (optionally having one substituting moiety β) or (xi)carboxyl group,

[0209] the substituting moiety β is a (i) C₁-C₄ alkyl group, (ii)halogen atom or (iii) phenylaminocarbonyl group (optionally having 1-3substituting moieties γ on the phenyl moiety), and

[0210] the substituting moiety γ is a trifluoromethyl group or a halogenatom), pharmacologically acceptable esters thereof, pharmacologicallyacceptable amides thereof or pharmacologically acceptable salts thereof.

[0211] (45) The α-substituted carboxylic acid derivatives (wherein R₁,R₂ and R₃ are the same or different, and each is a (i) hydrogen atom,(ii) C₁-C₄ alkyl group or (iii) benzyl group (optionally having onesubstituting moiety α₁ on the phenyl moiety thereof),

[0212] A is a ═CH-group,

[0213] B is an oxygen atom,

[0214] W₁ is a C₁-C₂ alkylene group,

[0215] W₂ is a methylene group,

[0216] X is a hydrogen atom,

[0217] Y is an oxygen atom or S(O)p group (wherein p is an integer of0-2),

[0218] Z₁ is a (i) C₁-C₂ alkoxy group, (ii) C₁-C₂ alkylthio group, (iii)phenoxy group (optionally having 1-5 substituting moieties α₁) (iv)saturated heterocyclic ring-oxy group (optionally having 1-5substituting moieties α₁), (v) phenylthio group (optionally having 1-5substituting moieties α₁) or (vi) hydroxy group), the substitutingmoiety α₁ is a (i) C₁-C₄ alkyl group, (ii) halogen atom, (iii) hydroxygroup, (iv) adamantyl group, (v) benzoyl group, (vi) amino group(optionally having one substituting moiety β) or (vii) carboxyl group,

[0219] the substituting moiety β is a phenylaminocarbonyl group(optionally having one substituting moiety γ on the phenyl moietythereof), and

[0220] the substituting moiety γ is a trifluoromethyl group,pharmacologically acceptable esters thereof, pharmacologicallyacceptable amides thereof or pharmacologically acceptable salts thereof.

[0221] Further, preferable embodiments of the α-substituted carboxylicacid derivatives of the general formula (II) above-described will beshown below.

[0222] (46) The α-substituted carboxylic acid derivatives (wherein Z₂ isa 5- or 6-member saturated heterocyclic ring group (optionally having1-5 substituting moieties α₁) or a phenyl group optionally having 1-3substituting moieties α₂), pharmacologically acceptable esters thereof,pharmacologically acceptable amides thereof or pharmacologicallyacceptable salts thereof.

[0223] (47) The α-substituted carboxylic acid derivatives (wherein Z₂ isa tetrahydropyranyl group (optionally having 1-5 substituting moietiesα₁)), pharmacologically acceptable esters thereof, pharmacologicallyacceptable amides thereof or pharmacologically acceptable salts thereof.

[0224] (48) The α-substituted carboxylic acid derivatives (wherein Z₂ isa phenyl group (optionally having one substituting moiety α₂),pharmacologically acceptable esters thereof, pharmacologicallyacceptable amides thereof or pharmacologically acceptable salts thereof.

[0225] (49) The α-substituted carboxylic acid derivatives (wherein thesubstituting moiety α₂ is a (i) C₆-C₁₀ cycloalkyl group, (ii) phenylgroup (optionally having 1-3 substituting moieties β)), (iii)phenylcarbonyl group (optionally having 1-3 substituting moieties β), or(iv) monocyclic type heteroaromatic ring-carbonyl group (optionallyhaving 1-3 substituting moieties β)), pharmacologically acceptableesters thereof, pharmacologically acceptable amides thereof orpharmacologically acceptable salts thereof.

[0226] (50) The α-substituted carboxylic acid derivatives (wherein thesubstituting moiety α₂ is a C₆-C₁₀ cycloalkyl group), pharmacologicallyacceptable esters thereof, pharmacologically acceptable amides thereofor pharmacologically acceptable salts thereof.

[0227] (51) The α-substituted carboxylic acid derivatives (wherein thesubstituting moiety α₂ is an adamantyl group), pharmacologicallyacceptable esters thereof, pharmacologically acceptable amides thereofor pharmacologically acceptable salts thereof.

[0228] Further, those compounds in which R₁, R₂ and R₃ are selected from(1)-(8) above, A is selected from (9) or (10) above, B is selected from(11) or (12) above, W₁ is selected from (13)-(16) above, W₂ is selectedfrom (17)-(20) above, X is selected from (21)-(23) above, Z₂ is selectedfrom (46)-(48) above, α₁ is selected from (28)-(36) above, α₂ isselected from (49)-(51) above, β is selected from (37)-(39) above and γis selected from (40)-(42) above in the α-substituted carboxylic acidderivatives of the general formula (II) are preferable.

[0229] For example, the following compounds in the α-substitutedcarboxylic acid derivatives of the general formula (II) are alsopreferable.

[0230] (52) The α-substituted carboxylic acid derivatives (wherein R₁,R₂ and R₃ are the same or different, and each is a (i) hydrogen atom,(ii) C₁-C₄ alkyl group, (iii) phenyl group (optionally having onesubstituting moiety α₁), (iv) phenyl-C₁-C₂ alkyl group (optionallyhaving 1-3 substituting moieties α₁ on the phenyl moiety thereof) or (v)C₁-C₂ alkylsulfonyl group,

[0231] A is a ═CH-group,

[0232] B is an oxygen atom,

[0233] W₁ is a C₁-C₄ alkylene group,

[0234] W₂ is a C₁-C₄ alkylene group,

[0235] X is a (i) hydrogen atom, (ii) C₁-C₂ alkyl group, (iii) halogenatom, (iv) hydroxy group, (v) C₁-C₂ aliphatic acyl group or (vi) aminogroup,

[0236] Y is an oxygen atom or S(O)p group (wherein p is an integer of0-2),

[0237] Z₂ is a 5- or 6-member saturated heterocyclic ring group(optionally having 1-5 substituting moieties α₁) or a phenyl group(optionally having 1-3 substituting moieties α₂),

[0238] the substituting moiety α₁ is a (i) C₁-C₄ alkyl group, (ii)halogen atom, (iii) hydroxy group, (iv) adamantyl group, (v) benzoylgroup, (vi) amino group (optionally having one substituting moiety β) or(vii) carboxyl group,

[0239] the substituting moiety α₂ is a C₆-C₁₀ cycloalkyl group,

[0240] the substituting moiety β is a (i) C₁-C₄ alkyl group, (ii)halogen atom or (iii) phenylaminocarbonyl group (optionally having 1-3substituting moieties γ on the phenyl moiety thereof), and

[0241] the substituting moiety γ is a trifluoromethyl group or a halogenatom, pharmacologically acceptable esters thereof, pharmacologicallyacceptable amides thereof or pharmacologically acceptable salts thereof.

[0242] (53) The α-substituted carboxylic acid derivatives (wherein R₁,R₂ and R₃ are the same or different, and each is a (i) hydrogen atom,(ii) C₁-C₄ alkyl group or (iii) benzyl group (optionally having onesubstituting moiety α₁ on the phenyl moiety thereof),

[0243] A is a ═CH-group,

[0244] B is an oxygen atom,

[0245] W₁ is a C₁-C₂ alkylene group,

[0246] W₂ is a C₁-C₂ alkylene group,

[0247] X is a hydrogen atom,

[0248] Y is an oxygen atom or S(O)p group (wherein p is an integer of0-2),

[0249] Z₂ is a tetrahydropyranyl group (optionally having 1-5substituting moieties α₁), and the substituting moieties α₁ is a hydroxygroup or a carboxyl group, pharmacologically acceptable esters thereof,pharmacologically acceptable amides thereof or pharmacologicallyacceptable salts thereof.

[0250] (54) The α-substituted carboxylic acid derivatives (wherein R₁,R₂ and R₃ are the same or different, and each is a (i) hydrogen atom,(ii) C₁-C₄ alkyl group or (iii) benzyl group (optionally having onesubstituting moiety α₁ on the phenyl moiety thereof),

[0251] A is a ═CH-group,

[0252] B is an oxygen atom,

[0253] W₁ is a C₁-C₂ alkylene group,

[0254] W₂ is a C₁-C₂ alkylene group,

[0255] X is a hydrogen atom,

[0256] Y is an oxygen atom or S(O)p group (wherein p is an integer of0-2),

[0257] Z₂ is a phenyl group (having one substituting moiety α₂),

[0258] the substituting moiety α₁ is a halogen atom or an adamantylgroup, and the substituting moiety α₂ is adamantyl, pharmacologicallyacceptable esters thereof, pharmacologically acceptable amides thereofor pharmacologically acceptable salts thereof.

[0259] Further, preferable embodiments of the α-substituted carboxylicacid derivatives of the general formula (III) will be shown below.

[0260] (55) The α-substituted carboxylic acid derivatives (wherein Z₃ isa (i) C₁-C₄ alkyl group, (ii) C₆-C₁₀ aryl group (optionally having 1-3substituting moieties α₁) or (iii) C₃-C₁₀ cycloalkyl group),pharmacologically acceptable esters thereof, pharmacologicallyacceptable amides thereof or pharmacologically acceptable salts thereof.

[0261] (56) The α-substituted carboxylic acid derivatives (wherein Z₃ isa C₁-C₄ alkyl group, phenyl group (optionally having 1-3 substitutingmoieties α₁) or C₃-C₁₀ cycloalkyl group), pharmacologically acceptableesters thereof, pharmacologically acceptable amides thereof orpharmacologically acceptable salts thereof.

[0262] (57) The α-substituted carboxylic acid derivatives (wherein Z₃ isa phenyl group (optionally having 1-3 substituting moieties α₁)),pharmacologically acceptable esters thereof, pharmacologicallyacceptable amides thereof or pharmacologically acceptable salts thereof.

[0263] Furthermore, those compounds in the α-substituted carboxylic acidderivatives of the general formula (III) in which R₁, R₂ and R₃ areselected from (1)-(8) above, A is selected from (9) or (10) above, B isselected from (11) or (12) above, W₁ is selected from (13)-(16) above,W₂ is selected from (17)-(20) above, X is selected from (21)-(23) above,Z₃ is selected from (55)-(57), α₁ is selected from (28)-(36) above, β isselected from (37)-(39) above, and γ is selected from (40)-(42) aboveare preferable. For examples, the following compounds in theα-substituted carboxylic acid derivatives of the general formula (III)are also preferable.

[0264] (58) The α-substituted carboxylic acid derivatives (wherein R₁,R₂ and R₃ are the same or different, and each is a (i) hydrogen atom,(ii) C₁-C₄ alkyl group or (iii) benzyl group (optionally having onesubstituting moiety α₁ on the phenyl moiety thereof)),

[0265] A is a ═CH-group,

[0266] B is an oxygen atom,

[0267] W₁ is a C₁-C₂ alkylene group,

[0268] W₂ is a C₁-C₂ alkylene group,

[0269] X is a hydrogen atom,

[0270] Y is an oxygen atom or S(O)p (wherein p is an integer of 0-2),

[0271] Z₃ is a (i) C₁-C₄ alkyl group, (ii) C₆-C₁₀ aryl group (optionallyhaving 1-3 substituting moieties α₁) or (iii) C₃-C₁₀ cycloalkyl group,and

[0272] the substituting moiety α₁ is a (i) C₁-C₄ alkyl group, (ii)halogen atom, (iii) hydroxy group or (iv) adamantyl group),pharmacologically acceptable esters thereof, pharmacologicallyacceptable amides thereof or pharmacologically acceptable salts thereof.

[0273] (59) The α-substituted carboxylic acid derivatives (wherein R₁ isa C₁-C₂ alkyl group, R₂ is a hydrogen atom, R₃ is a C₁-C₄ alkyl group ora phenyl-C₁-C₄ alkyl group (optionally having one substituting moiety α₁on the phenyl moiety thereof),

[0274] A is a ═CH-group,

[0275] B is an oxygen atom,

[0276] W₁ is a methylene group,

[0277] W₂ is a methylene group,

[0278] X is a hydrogen atom,

[0279] Y is an oxygen atom or S(O)p (wherein p is an integer of 0-2)

[0280] Z₃ is a phenyl group (optionally having 1-3 substituting moietiesα₁),

[0281] and the substituting moiety α₁ is a C₁-C₄ alkyl group or ahydroxy group), pharmacologically acceptable esters thereof,pharmacologically acceptable amides thereof or pharmacologicallyacceptable salts thereof.

[0282] Further, preferable embodiments in the α-substituted carboxylicacid derivatives of the general formula (IV) above-described will beshown below.

[0283] (60) The α-substituted carboxylic acid derivatives (wherein R₄ isa C₁-C₄ alkyl group or phenyl group (optionally having 1-3 substitutingmoieties α₁)), pharmacologically acceptable esters thereof,pharmacologically acceptable amides thereof or pharmacologicallyacceptable salts thereof.

[0284] (61) The α-substituted carboxylic acid derivatives (wherein R₄ isa phenyl group (optionally having one substituting moiety α₁)),pharmacologically acceptable esters thereof, pharmacologicallyacceptable amides thereof or pharmacologically acceptable salts thereof.

[0285] (62) The α-substituted carboxylic acid derivatives (wherein Z₄ isa (i) C₁-C₄ alkoxy group, (ii) C₁-C₄ alkylthio group (iii) C₆-C₁₀aryloxy group (optionally having 1-3 substituting moieties α₁), (iv)benzyloxy group (optionally having 1-3 substituting moieties α₁ on thephenyl moiety thereof), (v) C₆-C₁₀ arylthio group (optionally having 1-3substituting moieties α₁) or (vi) benzylthio group (optionally having1-5 substituting moieties α₁ on the phenyl moiety thereof)),pharmacologically acceptable esters thereof, pharmacologicallyacceptable amides thereof or pharmacologically acceptable salts thereof.

[0286] (63) The α-substituted carboxylic acid derivatives (wherein Z₄ isa (i) C₁-C₄ alkoxy group, (ii) C₁-C₂ alkylthio group, (iii) phenoxygroup (optionally having 1-3 substituting moieties α₁) (iv) phenylthiogroup (optionally having 1-3 substituting moieties α₁)),pharmacologically acceptable esters thereof, pharmacologicallyacceptable amides thereof or pharmacologically acceptable salts thereof.

[0287] (64) The α-substituted carboxylic acid derivatives (wherein Z₄ isa C₁-C₂ alkoxy group or a phenoxy group (optionally having 1-3substituting moieties α₁)), pharmacologically acceptable esters thereof,pharmacologically acceptable amides thereof or pharmacologicallyacceptable salts thereof.

[0288] (65) The α-substituted carboxylic acid derivatives (wherein Z₄ isa C₁-C₂ alkoxy group), pharmacologically acceptable esters thereof,pharmacologically acceptable amides thereof or pharmacologicallyacceptable salts thereof.

[0289] (66) The α-substituted carboxylic acid derivatives (wherein Z₄ isa phenoxy group (optionally having 1-3 substituting moieties α₁)),pharmacologically acceptable esters thereof, pharmacologicallyacceptable amides thereof or pharmacologically acceptable salts thereof.

[0290] Furthermore, those compounds in the α-substituted carboxylic acidderivatives of the general formula (IV) above-described in which R₁, R₂and R₃ are selected from (1)-(8) above, R₄ is selected from (60) or (61)above, A is selected from (9) or (10) above, B is selected from (11) or(12) above, W₁ is selected from (13)-(16) above, W₂ is selected from(17)-(20) above, X is selected from (21)-(23) above, Z₄ is selected from(62)-(66) above, α₁ is selected from (28)-(36), β is selected from(37)-(39), and γ is selected from (40)-(42) above are also preferable.

[0291] For example, the following compounds in the α-substitutedcarboxylic acid derivatives of the general formula (IV) above are alsopreferable.

[0292] (67) The α-substituted carboxylic acid derivatives (wherein R₁,R₂ and R₃ are the same or different, and each is a (i) hydrogen atom,(ii) C₁-C₄ alkyl group or (iii) benzyl group (optionally having onesubstituting moiety α₁ on the phenyl moiety thereof)),

[0293] R₄ is a C₁-C₄ alkyl group or a phenyl group (optionally having1-3 substituting moieties α₁),

[0294] A is a ═CH-group,

[0295] B is an oxygen atom,

[0296] W₁ is a C₁-C₂ alkylene group,

[0297] W₂ is a C₁-C₂ alkylene group,

[0298] X is a (i) hydrogen atom, (ii) C₁-C₂ alkyl group, (iii) halogenatom, (iv) hydroxy group, (v) C₁-C₂ aliphatic acyl group or (vi) aminogroup,

[0299] Z₄ is a (i) C₁-C₄ alkoxy group, (ii) C₁-C₂ alkylthio group, (iii)phenoxy group (optionally having 1-3 substituting moieties α₁) or (iv)phenylthio group (optionally having 1-3 substituting moieties α₁), and

[0300] the substituting moiety α₁ is a (i) C₁-C₄ alkyl group, (ii)halogen atom, (iii) hydroxy group, (iv) adamantyl group, (v) benzoylgroup, (vi) amino group (optionally having one substituting moiety β) or(vii) carboxyl group,

[0301] the substituting moiety β is a (i) C₁-C₄ alkyl group, (ii)halogen atom or (iii) phenylaminocarbonyl group (optionally having 1-3substituting moieties γ on the phenyl moiety thereof), and

[0302] the substituting moiety γ is a trifluoromethyl group or a halogenatom), pharmacologically acceptable esters thereof, pharmacologicallyacceptable amides thereof or pharmacologically acceptable salts thereof.

[0303] (68) The α-substituted carboxylic acid derivatives (wherein R₁ isa C₁-C₂ alkyl group,

[0304] R₂ is a hydrogen atom, R₃ is a hydrogen atom,

[0305] R₄ is a phenyl group (optionally having one substituting moietyα₁),

[0306] A is a ═CH-group,

[0307] B is an oxygen atom,

[0308] W₁ is a methylene group,

[0309] W₂ is methylene group,

[0310] X is a hydrogen atom,

[0311] Z₄ is a C₁-C₂ alkoxy group, and

[0312] the substituting moiety α₁ is a benzoyl group), pharmacologicallyacceptable esters thereof, pharmacologically acceptable amides thereofor pharmacologically acceptable salts thereof.

[0313] (69) The α-substituted carboxylic acid derivatives (wherein R₁ isa C₁-C₂ alkyl group,

[0314] R₂ is a hydrogen atom, R₃ is a hydrogen atom,

[0315] R₄ is a phenyl group (optionally having one substituting moietyα₁ ),

[0316] A is a ═CH-group,

[0317] B is an oxygen atom,

[0318] W₁ is a methylene group,

[0319] W₂ is a methylene group,

[0320] X is a hydrogen atom,

[0321] Z₄ is a phenoxy group (optionally having 1-3 substitutingmoieties α₁), the substituting moiety α₁ is a C₁-C₄ alkyl group, abenzoyl group or an amino group (optionally having one substitutingmoiety β),

[0322] the substituting moiety β is a phenylaminocarbonyl group(optionally having one substituting moiety γ on the phenyl moietythereof), and

[0323] the substituting moiety γ is a trifluoromethyl group),

[0324] pharmacologically acceptable esters thereof, pharmacologicallyacceptable amides thereof or pharmacologically acceptable salts thereof.

[0325] Examples of the α-substituted carboxylic acid derivatives of thepresent invention can be shown in Tables 1-5, but the scope of theinvention should not be limited by those compounds. Further, thecompounds in Tables 1-5 have each the chemical structure (I-1) to (I-5).The abbreviations in the tables have the following significance.

[0326] Ac: acetyl

[0327] Ada: adamantyl

[0328] Boz: benzoyl

[0329] Bu: butyl

[0330] iBu: isobutyl,

[0331] sBu: s-butyl

[0332] tBu: t-butyl,

[0333] Bz: benzyl

[0334] Byr: butyryl

[0335] iByr: isobutyryl

[0336] Car: carbamoyl

[0337] Et: ethyl

[0338] GlcA: β-D-glucopyranuranosyloxy

[0339] Hx: hexyl,

[0340] iHx: isohexyl

[0341] sHx: s-hexyl

[0342] cHx: cyclohexyl

[0343] Hynyl: hexanoyl

[0344] Imid: imidazolyl

[0345] Me: methyl

[0346] Mor: morpholinyl

[0347] Nic: nicotinoyl

[0348] iNic: isonicotinoyl

[0349] Np: naphthyl

[0350] Ph: phenyl

[0351] Pip: 1-piperidinyl

[0352] Pipra: piperazinyl

[0353] Pn: pentyl

[0354] cPn: cyclopentyl

[0355] cPnc: cyclopentylcarbonyl

[0356] Pr: propyl

[0357] cPr: cyclopropyl

[0358] iPr: isopropyl

[0359] Prn: propionyl

[0360] Pyr: pyridyl

[0361] Pyrd: pyrrolidinyl

[0362] TioMor: thiomorpholinylcarbonyl

[0363] Tos: p-toluenesulfonyl

[0364] Va: valeryl group

[0365] E.C.No.: exemplification compound number. TABLE 1

E.C.No. B X Y Z₁ R₁ R₂ R₃ m n 1-1 O H O 4-AdaPhO Me H 4-FBz 1 1 1-2 O HO 4-AdaPhO Me H 4-FBz 1 0 1-3 O H O 4-AdaPhO Me H 4-FBz 1 2 1-4 O H O4-AdaPhO Me H 4-FBz 1 3 1-5 O H O 4-AdaPhO Me H 4-FBz 1 4 1-6 O H O4-AdaPhO Me H 4-FBz 1 5 1-7 O H O 4-AdaPhO Me H 4-FBz 1 6 1-8 O H O4-AdaPhO Me H 4-FBz 1 7 1-9 O H O 4-AdaPhO Me H 4-FBz 1 8 1-10 O H O4-AdaPhO Me H 4-FBz 2 1 1-11 O H O 4-AdaPhO Me H 4-FBz 3 1 1-12 O H O4-AdaPhO Me H 4-FBz 4 1 1-13 O H O 4-AdaPhO Me H 4-FBz 5 1 1-14 O H O4-AdaPhO Me H 4-FBz 6 1 1-15 O H O 4-AdaPhO Me H 4-FBz 7 1 1-16 O H O4-AdaPhO Me H 4-FBz 8 1 1-17 O H S 4-AdaPhO Me H H 1 1 1-18 O H S4-AdaPhO Me H Me 1 1 1-19 O H S 4-AdaPhO Me H Et 1 1 1-20 O H S 4-AdaPhOMe H Bu 1 1 1-21 O H S 4-AdaPhO Me H Ph 1 1 1-22 O H S 4-AdaPhO Me H Bz1 1 1-23 O H S 4-AdaPhO Me H 4-ClBz 1 1 1-24 S H S 4-AdaPhO Me H 4-FBz 11 1-25 O H O 4-AdaPhO Me H 4-FBz 1 1 1-26 O H S 4-AdaPhO 4-FBz H 4-FBz 11 1-27 O H S 4-AdaPhO Et H 4-FBz 1 1 1-28 O H S 4-AdaPhO Pr H 4-FBz 1 11-29 O H S 4-AdaPhO iPr H 4-FBz 1 1 1-30 O H S 4-AdaPhO Bu H 4-FBz 1 11-31 O H S 4-AdaPhO iBu H 4-FBz 1 1 1-32 O H S 4-AdaPhO sBu H 4-FBz 1 11-33 O H S 4-AdaPhO Pn H 4-FBz 1 1 1-34 O H S 4-AdaPhO Hx H 4-FBz 1 11-35 O H S 4-AdaPhO Ph H 4-FBz 1 1 1-36 O H S 4-AdaPhO Bz H 4-FBz 1 11-37 O H S 4-AdaPhO Me Me 4-FBz 1 1 1-38 O H S 4-AdaPhO Me Et 4-FBz 1 11-39 O H S 4-AdaPhO Me Pr 4-FBz 1 1 1-40 O H S 4-AdaPhO Me iPr 4-FBz 1 11-41 O H S 4-AdaPhO Me Bu 4-FBz 1 1 1-42 O H S 4-AdaPhO Me iBu 4-FBz 1 11-43 O H S 4-AdaPhO Me SBu 4-FBz 1 1 1-44 O H S 4-AdaPhO Me Pn 4-FBz 1 11-45 O H S 4-AdaPhO Me Hx 4-FBz 1 1 1-46 O H S 4-AdaPhO Me Ph 4-FBz 1 11-47 O H S 4-AdaPhO Me 4-FPh 4-FBz 1 1 1-48 O H S 4-AdaPhO Me 3-CF₃Ph4-FBz 1 1 1-49 O H S 4-AdaPhO Me 3-MeOPh 4-FBz 1 1 1-50 O H S 4-AdaPhOMe 2-MePh 4-FBz 1 1 1-51 O H S 4-AdaPhO Me 4-CNPh 4-FBz 1 1 1-52 O H S4-AdaPhO Me Bz 4-FBz 1 1 1-53 O H S 4-AdaPhO Me 3-FBz 4-FBz 1 1 1-54 O HS 4-AdaPhO Me 2-CF₃Bz 4-FBz 1 1 1-55 O H S 4-AdaPhO Me 3,5-diMeOBz 4-FBz1 1 1-56 O H S 4-AdaPhO Me 4-ClBz 4-FBz 1 1 1-57 O Cl S 4-AdaPhO Me H4-FBz 1 1 1-58 O F S 4-AdaPhO Me H 4-FBz 1 1 1-59 O Br S 4-AdaPhO Me H4-FBz 1 1 1-60 O Me S 4-AdaPhO Me H 4-FBz 1 1 1-61 O MeO S 4-AdaPhO Me H4-FBz 1 1 1-62 O EtO S 4-AdaPhO Me H 4-FBz 1 1 1-63 O iPr S 4-AdaPhO MeH 4-FBz 1 1 1-64 O CF₃ S 4-AdaPhO Me H 4-FBz 1 1 1-65 O HO S 4-AdaPhO MeH 4-FBz 1 1 1-66 O EtO S 4-AdaPhO Me H 4-FBz 1 1 1-67 O tBu S 4-AdaPhOMe H 4-FBz 1 1 1-68 O Ac S 4-AdaPhO Me H 4-FBz 1 1 1-69 O Boz S 4-AdaPhOMe H 4-FBz 1 1 1-70 O PhAc S 4-AdaPhO Me H 4-FBz 1 1 1-71 O cPnc S4-AdaPhO Me H 4-FBz 1 1 1-72 O NH₂ S 4-AdaPhO Me H 4-FBz 1 1 1-73 O NHAcS 4-AdaPhO Me H 4-FBz 1 1 1-74 O NHBoz S 4-AdaPhO Me H 4-FBz 1 1 1-75 ONHMe S 4-AdaPhO Me H 4-FBz 1 1 1-76 O NHiPr S 4-AdaPhO Me H 4-FBz 1 11-77 O NHPh S 4-AdaPhO Me H 4-FBz 1 1 1-78 O NHBz S 4-AdaPhO Me H 4-FBz1 1 1-79 O NMeEt S 4-AdaPhO Me H 4-FBz 1 1 1-80 O NEtPh S 4-AdaPhO Me H4-FBz 1 1 1-81 O NPhBz S 4-AdaPhO Me H 4-FBz 1 1 1-82 O Ph S 4-AdaPhO MeH 4-FBz 1 1 1-83 O Np S 4-AdaPhO Me H 4-FBz 1 1 1-84 O CN S 4-AdaPhO MeH 4-FBz 1 1 1-85 O NO₂ S 4-AdaPhO Me H 4-FBz 1 1 1-86 O H O 4-HO-3,5-di-Me H 4-FBz 1 1 tBuPhS 1-87 O H O 4-HO-3,5-di- Me H H 1 1 tBuPhS 1-88 O HS 4-HO-3,5-di- Me H Me 1 1 tBuPhS 1-89 O H S 4-HO-3,5-di- Me H Et 1 1tBuPhS 1-90 O H S 4-HO-3,5-di- Me H Hx 1 1 tBuPhS 1-91 O H S4-HO-3,5-di- Me H Bz 1 1 tBuPhS 1-92 O H O 4-HO-3,5-di- Me H Ph 1 1tBuPhS 1-93 O H O 4-HO-3,5-di- Me H 4-FBz 1 0 tBuPhS 1-94 O H O4-HO-3,5-di- Me H 4-FBz 1 2 tBuPhS 1-95 O H O 4-HO-3,5-di- Me H 4-FBz 13 tBuPhS 1-96 O H O 4-HO-3,5-di- Me H 4-FBz 1 4 tBuPhS 1-97 O H O4-HO-3,5-di- Me H 4-FBz 1 5 tBuPhS 1-98 O H O 4-HO-3,5-di- Me H 4-FBz 16 tBuPhS 1-99 O H O 4-HO-3,5-di- Me H 4-FBz 1 7 tBuPhS 1-100 O H O4-HO-3,5-di- Me H 4-FBz 1 8 tBuPhS 1-101 O H O 4-HO-3,5-di- Me H 4-FBz 21 tBuPhS 1-102 O H O 4-HO-3,5-di- Me H 4-FBz 3 1 tBuPhS 1-103 O H O4-HO-3,5-di- Me H 4-FBz 4 1 tBuPhS 1-104 O H O 4-HO-3,5-di- Me H 4-FBz 51 tBuPhS 1-105 O H O 4-HO-3,5-di- Me H 4-FBz 6 1 tBuPhS 1-106 O H O4-HO-3,5-di- Me H 4-FBz 7 1 tBuPhS 1-107 O H O 4-HO-3,5-di- Me H 4-FBz 81 tBuPhS 1-108 S H S 4-HO-3,5-di- Me H 4-FBz 1 1 tBuPhS 1-109 O H O4-HO-3,5-di- Me H 4-FBz 1 1 BuPhS 1-110 O H S 4-HO-3,5-di- Me H 4-FBz 11 tBuPhO 1-111 O H S 4-HO-3,5-di- Et H 4-FBz 1 1 tBuPhS 1-112 O H S4-HO-3,5-di- Pr H 4-FBz 1 1 tBuPhS 1-113 O H S 4-HO-3,5-di- iPr H 4-FBz1 1 tBuPhS 1-114 O H S 4-HO-3,5-di- Bu H 4-FBz 1 1 tBuPhS 1-115 O H S4-HO-3,5-di- iBu H 4-FBz 1 1 tBuPhS 1-116 O H S 4-HO-3,5-di- sBu H 4-FBz1 1 tBuPhS 1-117 O H S 4-HO-3,5-di- Hx H 4-FBz 1 1 tBuPhS 1-118 O H S4-HO-3,5-di- Hx H 4-FBz 1 1 tBuPhS 1-119 O H S 4-HO-3,5-di- Ph H 4-FBz 11 tBuPhS 1-120 O H S 4-HO-3,5-di- Bz H 4-FBz 1 1 tBuPhS 1-121 O H S4-HO-3,5-di- Me Me 4-FBz 1 1 tBuPhS 1-122 O H S 4-HO-3,5-di- Me Et 4-FBz1 1 tBuPhS 1-123 O H S 4-HO-3,5-di- Me Pr 4-FBz 1 1 tBuPhS 1-124 O H S4-HO-3,5-di- Me iPr 4-FBz 1 1 tBuPhS 1-125 O H S 4-HO-3,5-di- Me Bu4-FBz 1 1 tBuPhS 1-126 O H S 4-HO-3,5-di- Me iBu 4-FBz 1 1 tBuPhS 1-127O H S 4-HO-3,5-di- Me sBu 4-FBz 1 1 tBuPhS 1-128 O H S 4-HO-3,5-di- MePn 4-FBz 1 1 tBuPhS 1-129 O H S 4-HO-3,5-di- Me Hx 4-FBz 1 1 tBuPhS1-130 O H S 4-HO-3,5-di- Me Ph 4-FBz 1 1 tBuPhS 1-131 O H S 4-HO-3,5-di-Me 4-FPh 4-FBz 1 1 tBuPhS 1-132 O H S 4-HO-3,5-di- Me 3-CF₃Ph 4-FBz 1 1tBuPhS 1-133 O H S 4-HO-3,5-di- Me 3-MeOPh 4-FBz 1 1 tBuPhS 1-134 O H S4-HO-3,5-di- Me 2-MePh 4-FBz 1 1 tBuPhS 1-135 O H S 4-HO-3,5-di- Me4-CNPh 4-FBz 1 1 tBuPhS 1-136 O H S 4-HO-3,5-di- Me Bz 4-FBz 1 1 tBuPhS1-137 O H S 4-HO-3,5-di- Me 3-FBz 4-FBz 1 1 tBuPhS 1-138 O H S4-HO-3,5-di- Me 2-CF₃Bz 4-FBz 1 1 tBuPhS 1-139 O H S 4-HO-3,5-di- Me3,5-diMeOBz 4-FBz 1 1 tBuPhS 1-140 O H S 4-HO-3,5-di- Me 4-ClBz 4-FBz 11 tBuPhS 1-141 O Cl S 4-HO-3,5-di- Me H 4-FBz 1 1 tBuPhS 1-142 O F S4-HO-3,5-di- Me H 4-FBz 1 1 tBuPhS 1-143 O Br S 4-HO-3,5-di- Me H 4-FBz1 1 tBuPhS 1-144 O Me S 4-HO-3,5-di- Me H 4-FBz 1 1 tBuPhS 1-145 O MeO S4-HO-3,5-di- Me H 4-FBz 1 1 tBuPhS 1-146 O EtO S 4-HO-3,5-di- Me H 4-FBz1 1 tBuPhS 1-147 O iPr S 4-HO-3,5-di- Me H 4-FBz 1 1 tBuPhS 1-148 O CF₃S 4-HO-3,5-di- Me H 4-FBz 1 1 tBuPhS 1-149 O HO S 4-HO-3,5-di- Me H4-FBz 1 1 tBuPhS 1-150 O EtO S 4-HO-3,5-di- Me H 4-FBz 1 1 tBuPhS 1-151O tBu S 4-HO-3,5-di- Me H 4-FBz 1 1 tBuPhS 1-152 O Ac S 4-HO-3,5-di- MeH 4-FBz 1 1 tBuPhS 1-153 O Boz S 4-HO-3,5-di- Me H 4-FBz 1 1 tBuPhS1-154 O PhAc S 4-HO-3,5-di- Me H 4-FBz 1 1 tBuPhS 1-155 O cPnc S4-HO-3,5-di- Me H 4-FBz 1 1 tBuPhS 1-156 O NH₂ S 4-HO-3,5-di- Me H 4-FBz1 1 tBuPhS 1-157 O NHAc S 4-HO-3,5-di- Me H 4-FBz 1 1 tBuPhS 1-158 ONHBoz S 4-HO-3,5-di- Me H 4-FBz 1 1 tBuPhS 1-159 O NHMe S 4-HO-3,5-di-Me H 4-FBz 1 1 tBuPhS 1-160 O NHiPr S 4-HO-3,5-di- Me H 4-FBz 1 1 tBuPhS1-161 O NHPh S 4-HO-3,5-di- Me H 4-FBz 1 1 tBuPhS 1-162 O NHBz S4-HO-3,5-di- Me H 4-FBz 1 1 tBuPhS 1-163 O NMeEt S 4-HO-3,5-di- Me H4-FBz 1 1 tBuPhS 1-164 O NEtPh S 4-HO-3,5-di- Me H 4-FBz 1 1 tBuPhS1-165 O NPhBz S 4-HO-3,5-di- Me H 4-FBz 1 1 tBuPhS 1-166 O Ph S4-HO-3,5-di- Me H 4-FBz 1 1 tBuPhS 1-167 O Np S 4-HO-3,5-di- Me H 4-FBz1 1 tBuPhS 1-168 O CN S 4-HO-3,5-di- Me H 4-FBz 1 1 tBuPhS 1-169 O NO₂ S4-HO-3,5-di- Me H 4-FBz 1 1 tBuPhS 1-170 O H O 4-HO-2,3,5- Me H H 1 1triMePhO 1-171 O H O 4-HO-2,3,5- Me H Me 1 1 triMePhO 1-172 O H O4-HO-2,3,5- Me H Et 1 1 triMePhO 1-173 O H O 4-HO-2,3,5- Me H Bu 1 1triMePhO 1-174 O H O 4-HO-2,3,5- Me H Ph 1 1 triMePhO 1-175 O H O4-HO-2,3,5- Me H Bz 1 1 triMePhO 1-176 O H S 4-HO-2,3,5- Me H Bz 1 1triMePhO 1-177 O H O MeO Me H H 1 1 1-178 O H O MeO Me H Me 1 1 1-179 OH O MeO Me H Et 1 1 1-180 O H O MeO Me H Pr 1 1 1-181 O H O MeO Me H iPr1 1 1-182 O H O MeO Me H Pn 1 1 1-183 O H O MeO Me H Hx 1 1 1-184 O H OMeO Me H Bz 1 1 1-185 O H O MeO Me H 4-FBz 1 1 1-186 O H O MeO Me H3-ClBz 1 1 1-187 O H O MeO Me H Ph 1 1 1-188 O H O EtO Me H Bz 1 1 1-189O H O PrO Me H Bz 1 1 1-190 O H O iPrO Me H Bz 1 1 1-191 O H O BuO Me HBz 1 1 1-192 O H O iBuO Me H Bz 1 1 1-193 O H O sBuO Me H Bz 1 1 1-194 OH O tBuO Me H Bz 1 1 1-195 O H O PnO Me H Bz 1 1 1-196 O H O HxG Me H Bz1 1 1-197 O H O PhO Me H Bz 1 1 1-198 O H O 4-ClPhO Me H Bz 1 1 1-199 OH O 4-FPhG Me H Bz 1 1 1-200 O H O 2-FPhG Me H Bz 1 1 1-201 O H O 3-FPhOMe H Bz 1 1 1-202 O H O 4-CF₃PhO Me H Bz 1 1 1-203 O H O 3-CF₃PhO Me HBz 1 1 1-204 O H O 4-MeOPhP Me H Bz 1 1 1-205 O H O 4-MePhP Me H Bz 1 11-206 O H O 4-PhPhO Me H Bz 1 1 1-207 O H O 3-HOPhO Me H Bz 1 1 1-208 OH O 3-AcPhO Me H Bz 1 1 1-209 O H O 4-cPrPhO Me H Bz 1 1 1-210 O H O4-Me₂NPhO Me H Bz 1 1 1-211 O H O 4-CNPhO Me H Bz 1 1 1-212 O H O4-NO₂PhO Me H Bz 1 1 1-213 O H O Me Me H Bz 1 1 1-214 O H O Et Me H Bz 11 1-215 O H O tBu Me H Bz 1 1 1-216 O H O Hx Me H Bz 1 1 1-217 O H O PhMe H Bz 1 1 1-218 O H O Np Me H Bz 1 1 1-219 O H O 4-MeOPh Me H Bz 1 11-220 O H O Bz Me H Bz 1 1 1-221 O H O 4-CF₃Bz Me H Bz 1 1 1-122 O H OMeS Me H Bz 1 1 1-123 O H O PhS Me H Bz 1 1 1-124 O H O BzS Me H Bz 1 11-125 O H O 4-FPhS Me H Bz 1 1 1-226 O H O 4-CF₃PhS Me H Bz 1 1 1-227 OH O 4-FBzS Me H Bz 1 1 1-228 O H O F Me H Bz 1 1 1-229 O H O Cl Me H Bz1 1 1-23O O H O Br Me H Bz 1 1 1-231 O H O 2-PyrS Me H Bz 1 1 1-232 O HO 3-PyrS Me H 4-FBz 1 1 1-233 O H O 4-PyrS Me H 4-CF₃Bz 1 1 1-234 O H O2-PyrO Me H 3-MeOBz 1 1 1-235 O H O 3-PyrO Me H Bz 1 1 1-236 O H O4-PyrO Me H Bz 1 1 1-237 O H O cPrS Me H Bz 1 1 1-238 O H O cHxS Me H Bz1 1 1-239 O H O NH₂ Me H Bz 1 1 1-240 O H O NHMe Me H Bz 1 1 1-241 O H ONMeEt Me H Bz 1 1 1-242 O H O NHAc Me H Bz 1 1 1-243 O H O NHPh Me H Bz1 1 1-244 O H O NHBz Me H Bz 1 1 1-245 O H O NHBoz Me H Bz 1 1 1-246 O HO NMeBoz Me H Bz 1 1 1-247 O H O NEtBz Me H Bz 1 1 1-248 O H O NPhBz MeH Bz 1 1 1-249 O H O NPhBoz Me H Bz 1 1 1-250 O H O NH(4-FBoz) Me H Bz 11 1-251 O H O NH(3-MeBoz) Me H Bz 1 1 1-252 O H O NHBoz Me Me Bz 1 11-253 O H O NHBoz Me Et Bz 1 1 1-254 O H O NHBoz Me Ph Bz 1 1 1-255 O HO NHBoz Me Bz Bz 1 1

[0366] TABLE 2

E.C.No. B X Y Z₁ R₁ R₂ R₃ m n 2-1 O H S 4-AdaPhO Me H 4-FBz 1 1 2-2 O HS 4-AdaPhO Me H 4-FBz 1 0 2-3 O H S 4-AdaPhO Me H 4-FBz 1 2 2-4 O H S4-AdaPhO Me H 4-FBz 1 3 2-5 O H S 4-AdaPhO Me H 4-FBz 1 4 2-6 O H S4-AdaPhO Me H 4-FBz 1 5 2-7 O H S 4-AdaPhO Me H 4-FBz 1 6 2-8 O H S4-AdaPhO Me H 4-FBz 1 7 2-9 O H S 4-AdaPhO Me H 4-FBz 1 8 2-10 O H S4-AdaPhO Me H 4-FBz 2 1 2-11 O H S 4-AdaPhO Me H 4-FBz 3 1 2-12 O H S4-AdaPhO Me H 4-FBz 4 1 2-13 O H S 4-AdaPhO Me H 4-FBz 5 1 2-14 O H S4-AdaPhO Me H 4-FBz 6 1 2-15 O H S 4-AdaPhO Me H 4-FBz 7 1 2-16 O H S4-AdaPhO Me H 4-FBz 8 1 2-17 O NPhBz S 4-AdaPhO Me H 4-FBz 1 1 2-18 ONPhBz S 4-AdaPhO Me H 4-FBz 1 0 2-19 O NPhBz S 4-AdaPhO Me H 4-FBz 1 22-20 O NPhBz S 4-AdaPhO Me H 4-FBz 1 3 2-21 O NPhBz S 4-AdaPhO Me H4-FBz 1 4 2-22 O NPhBz S 4-AdaPhO Me H 4-FBz 1 5 2-23 O NPhBz S 4-AdaPhOMe H 4-FBz 1 6 2-24 O NPhBz S 4-AdaPhO Me H 4-FBz 1 7 2-25 O NPhBz S4-AdaPhO Me H 4-FBz 1 8 2-26 O NPhBz S 4-AdaPhO Me H 4-FBz 2 1 2-27 ONPhBz S 4-AdaPhO Me H 4-FBz 3 1 2-28 O NPhBz S 4-AdaPhO Me H 4-FBz 4 12-29 O NPhBz S 4-AdaPhO Me H 4-FBz 5 1 2-30 O NPhBz S 4-AdaPhO Me H4-FBz 6 1 2-31 O NPhBz S 4-AdaPhO Me H 4-FBz 7 1 2-32 O NPhBz S 4-AdaPhOMe H 4-FBz 8 1 2-33 O H S 4-HO-3,5-di- Me H 4-FBz 1 1 tBuPhS 2-34 O H S4-HO-3,5-di- Me H 4-FBz 1 0 tBuPhS 2-35 O H S 4-HO-3,5-di- Me H 4-FBz 12 tBuPhS 2-36 O H S 4-HO-3,5-di- Me H 4-FBz 1 3 tBuPhS 2-37 O H S4-HO-3,5-di- Me H 4-FBz 1 4 tBuPhS 2-38 O H S 4-HO-3,5-di- Me H 4-FBz 15 tBuPhS 2-39 O H S 4-HO-3,5-di- Me H 4-FBz 1 6 tBuPhS 2-40 O H S4-HO-3,5-di- Me H 4-FBz 1 7 tBuPhS 2-41 O H S 4-HO-3,5-di- Me H 4-FBz 18 tBuPhS 2-42 O H S 4-HO-3,5-di- Me H 4-FBz 2 1 tBuPhS 2-43 O H S4-HO-3,5-di- Me H 4-FBz 3 1 tBuPhS 2-44 O H S 4-HO-3,5-di- Me H 4-FBz 41 tBuPhS 2-45 O H S 4-HO-3,5-di- Me H 4-FBz 5 1 tBuPhS 2-46 O H S4-HO-3,5-di- Me H 4-FBz 6 1 tBuPhS 2-47 O H S 4-HO-3,5-di- Me H 4-FBz 71 tBuPhS 2-48 O H S 4-HO-3,5-di- Me H 4-FBz 8 1 tBuPhS 2-49 O NPhBz S4-HO-3,5-di- Me H 4-FBz 1 1 tBuPhS 2-50 O NPhBz S 4-HO-3,5-di- Me H4-FBz 1 0 tBuPhS 2-51 O NPhBz S 4-HO-3,5-di- Me H 4-FBz 1 2 tBuPhS 2-52O NPhBz S 4-HO-3,5-di- Me H 4-FBz 1 3 tBuPhS 2-53 O NPhBz S 4-HO-3,5-di-Me H 4-FBz 1 4 tBuPhS 2-54 O NPhBz S 4-HO-3,5-di- Me H 4-FBz 1 5 tBuPhS2-55 O NPhBz S 4-HO-3,5-di- Me H 4-FBz 1 6 tBuPhS 2-56 O NPhBz S4-HO-3,5-di- Me H 4-FBz 1 7 tBuPhS 2-57 O NPhBz S 4-HO-3,5-di- Me H4-FBz 1 8 tBuPhS 2-58 O NPhBz S 4-HO-3,5-di- Me H 4-FBz 2 1 tBuPhS 2-59O NPhBz S 4-HO-3,5-di- Me H 4-FBz 3 1 tBuPhS 2-60 O NPhBz S 4-HO-3,5-di-Me H 4-FBz 4 1 tBuPhS 2-61 O NPhBz S 4-HO-3,5-di- Me H 4-FBz 5 1 tBuPhS2-62 O NPhBz S 4-HO-3,5-di- Me H 4-FBz 6 1 tBuPhS 2-63 O NPhBz S4-HO-3,5-di- Me H 4-FBz 7 1 tBuPhS 2-64 O NPhBz S 4-HO-3,5-di- Me H4-FBz 8 1

[0367] TABLE 3

E.C.No. B X R₄ Z₄ R₁ R₂ R₃ m n 3-1 O H Me 4-AdaPhO Me H 4-FBz 1 1 3-2 OH Me 4-AdaPhO Me H 4-FBz 1 0 3-3 O H Et 4-AdaPhO Me H 4-FBz 1 2 3-4 O HPr 4-AdaPhO Me H 4-FBz 1 3 3-5 O H iPr 4-AdaPhO Me H 4-FBz 1 4 3-6 O HBu 4-AdaPhO Me H 4-FBz 1 5 3-7 O H iBu 4-AdaPhO Me H 4-FBz 1 6 3-8 O HsBu 4-AdaPhO Me H 4-FBz 1 7 3-9 O H tBu 4-AdaPhO Me H 4-FBz 1 8 3-10 O HPn 4-AdaPhO Me H 4-FBz 2 1 3-11 O H iPn 4-AdaPhO Me H 4-FBz 3 1 3-12 O HsPn 4-AdaPhO Me H 4-FBz 4 1 3-13 O H Hx 4-AdaPhO Me H 4-FBz 5 1 3-14 O HiHx 4-AdaPhO Me H 4-FBz 6 1 3-15 O H sHx 4-AdaPhO Me H 4-FBz 7 1 3-16 OH Ph 4-AdaPhO Me H 4-FBz 8 1 3-17 O H 4-FPh 4-AdaPhO Me H H 1 1 3-18 O H4-ClPh 4-AdaPhO Me H Me 1 1 3-19 O H 3-CF₃Ph 4-AdaPhO Me H Et 1 1 3-20 OH 2-MePh 4-AdaPhO Me H Bu 1 1 3-21 O H 3-MeOPh 4-AdaPhO Me H Ph 1 1 3-22O H 2-FPh 4-AdaPhO Me H Bz 1 1 3-23 O H Bz 4-AdaPhO Me H 4-ClBz 1 1 3-24S H 2-ClBz 4-AdaPhO Me H 4-FBz 1 1 3-25 O H 4-ClBz 4-AdaPhO Me H 4-FBz 11 3-26 O H 2-FBz 4-AdaPhO 4-FBz H 4-FBz 1 1 3-27 O H 3-FBz 4-AdaPhO Et H4-FBz 1 1 3-28 O H 4-FBz 4-AdaPhO Pr H 4-FBz 1 1 3-29 O H 2-CF₃Bz4-AdaPhO iPr H 4-FBz 1 1 3-30 O H 3-CF₃Bz 4-AdaPhO Bu H 4-FBz 1 1 3-31 OH 4-CF₃Bz 4-AdaPhO iBu H 4-FBz 1 1 3-32 O H 2-MeBz 4-AdaPhO sBu H 4-FBz1 1 3-33 O H 3-MeBz 4-AdaPhO Pn H 4-FBz 1 1 3-34 O H 4-MeBz 4-AdaPhO HxH 4-FBz 1 1 3-35 O H 2-MeOBz 4-AdaPhO Ph H 4-FBz 1 1 3-36 O H 3-MeOBz4-AdaPhO Bz H 4-FBz 1 1 3-37 O H 2-BozPh 4-AdaPhO Me Me 4-FBz 1 1 3-38 OH 2-BozPh 4-AdaPhO Me Et 4-FBz 1 1 3-39 O H 2-BozPh 4-AdaPhO Me Pr 4-FBz1 1 3-40 O H 2-BozPh 4-AdaPhO Me iPr 4-FBz 1 1 3-41 O H 2-BozPh 4-AdaPhOMe Bu 4-FBz 1 1 3-42 O H 2-BozPh 4-AdaPhO Me iBu 4-FBz 1 1 3-43 O H2-BozPh 4-AdaPhO Me sBu 4-FBz 1 1 3-44 O H 2-BozPh 4-AdaPhO Me Pn 4-FBz1 1 3-45 O H 2-BozPh 4-AdaPhO Me Hx 4-FBz 1 1 3-46 O H 2-BozPh 4-AdaPhOMe Ph 4-FBz 1 1 3-47 O H 2-BozPh 4-AdaPhO Me 4-FPh 4-FBz 1 1 3-48 O H2-BozPh 4-AdaPhO Me 3-CF₃Ph 4-FBz 1 1 3-49 O H 2-BozPh 4-AdaPhO Me3-MeOPh 4-FBz 1 1 3-50 O H 2-BozPh 4-AdaPhO Me 2-MePh 4-FBz 1 1 3-51 O H2-BozPh 4-AdaPhO Me 4-CNPh 4-FBz 1 1 3-52 O H 2-BozPh 4-AdaPhO Me Bz4-FBz 1 1 3-53 O H 2-BozPh 4-AdaPhO Me 3-FBz 4-FBz 1 1 3-54 O H 2-BozPh4-AdaPhO Me 2-CF₃Bz 4-FBz 1 1 3-55 O H 2-BozPh 4-AdaPhO Me 3,5-diMeOBz4-FBz 1 1 3-56 O H 2-BozPh 4-AdaPhO Me 4-ClBz 4-FBz 1 1 3-57 O Cl2-BozPh 4-AdaPhO Me H 4-FBz 1 1 3-58 O F 2-BozPh 4-AdaPhO Me H 4-FBz 1 13-59 O Br 2-BozPh 4-AdaPhO Me H 4-FBz 1 1 3-60 O Me 2-BozPh 4-AdaPhO MeH 4-FBz 1 1 3-61 O MeO 2-BozPh 4-AdaPhO Me H 4-FBz 1 1 3-62 O EtO2-BozPh 4-AdaPhO Me H 4-FBz 1 1 3-63 O iPr 2-BozPh 4-AdaPhO Me H 4-FBz 11 3-64 O CF₃ 2-BozPh 4-AdaPhO Me H 4-FBz 1 1 3-65 O HO 2-BozPh 4-AdaPhOMe H 4-FBz 1 1 3-66 O EtO 2-BozPh 4-AdaPhO Me H 4-FBz 1 1 3-67 O tBu2-BozPh 4-AdaPhO Me H 4-FBz 1 1 3-68 O Ac 2-BozPh 4-AdaPhO Me H 4-FBz 11 3-69 O Boz 2-BozPh 4-AdaPhO Me H 4-FBz 1 1 3-70 O PhAc 2-BozPh4-AdaPhO Me H 4-FBz 1 1 3-71 O cPnc 2-BozPh 4-AdaPhO Me H 4-FBz 1 1 3-72O NH₂ 2-BozPh 4-AdaPhO Me H 4-FBz 1 1 3-73 O NHAc 2-BozPh 4-AdaPhO Me H4-FBz 1 1 3-74 O NHBoz 2-BozPh 4-AdaPhO Me H 4-FBz 1 1 3-75 O NHMe Me4-AdaPhO Me H 4-FBz 1 1 3-76 O NHiPr Me 4-AdaPhO Me H 4-FBz 1 1 3-77 ONHPh Et 4-AdaPhO Me H 4-FBz 1 1 3-78 O NHBz Pr 4-AdaPhO Me H 4-FBz 1 13-79 O NMeEt iPr 4-AdaPhO Me H 4-FBz 1 1 3-80 O NEtPh Bu 4-AdaPhO Me H4-FBz 1 1 3-81 O NPhBz iBu 4-AdaPhO Me H 4-FBz 1 1 3-82 O Ph sBu4-AdaPhO Me H 4-FBz 1 1 3-83 O Np tBu 4-AdaPhO Me H 4-FBz 1 1 3-84 O CNPn 4-AdaPhO Me H 4-FBz 1 1 3-85 O NO₂ iPn 4-AdaPhO Me H 4-FBz 1 1 3-86 OH Hx 4-HO-3,5-di- Me H 4-FBz 1 1 tBuPhS 3-87 O H iHx 4-HO-3,5-di- Me H H1 1 tBuPhS 3-88 O H sHx 4-HO-3,5-di- Me H Me 1 1 tBuPhS 3-89 O H Ph4-HO-3,5-di- Me H Et 1 1 tBuPhS 3-90 O H 4-FPh 4-HO-3,5-di- Me H Hx 1 1tBuPhS 3-91 O H 4-ClPh 4-HO-3,5-di- Me H Bz 1 1 tBuPhS 3-92 O H 3-CF₃Ph4-HO-3,5-di- Me H Ph 1 1 tBuPhS 3-93 O H 2-MePh 4-HO-3,5-di- Me H 4-FBz1 0 tBuPhS 3-94 O H 3-MeOPh 4-HO-3,5-di- Me H 4-FBz 1 2 tBuPhS 3-95 O H2-FPh 4-HO-3,5-di- Me H 4-FBz 1 3 tBuPhS 3-96 O H Bz 4-HO-3,5-di- Me H4-FBz 1 4 tBuPhS 3-97 O H 3-ClBz 4-HO-3,5-di- Me H 4-FBz 1 5 tBuPhS 3-98O H 2-ClBz 4-HO-3,5-di- Me 4-FBz 1 6 tBuPhS 3-99 O H 2-ClBz 4-HO-3,5-di-Me 4-FBz 1 7 tBuPhS 3-100 O H 2-FBz 4-HO-3,5-di- Me 4-FBz 1 8 tBuPhS3-101 O H 3-FBz 4-HO-3,5-di- Me 4-FBz 2 1 tBuPhS 3-102 O H 4-FBz4-HO-3,5-di- Me 4-FBz 3 1 tBuPhS 3-103 O H 2-CF₃Bz 4-HO-3,S-di- Me 4-FBz4 1 tBuPhS 3-104 O H 3-CF₃Bz 4-HO-3,5-di- Me 4-FBz 5 1 tBuPhS 3-105 O H4-CF₃Bz 4-HO-3,5-di- Me 4-FBz 6 1 tBuPhS 3-106 O H 2-MeBz 4-HO-3,5-di-Me 4-FBz 7 1 tBuPhS 3-107 O H 3-MeBz 4-HO-3,5-di- Me H 4-FBz 8 1 tBuPhS3-108 S H 2-MeOBz 4-HO-3,5-di- Me H 4-FBz 1 1 BuPhS 3-108 S H 2-MeOBz4-HO-3,5-di- Me H 4-FBz 1 1 tBuPhS 3-109 O H 3-MeOBz 4-HO-3,5-di- Me H4-FBz 1 1 BuPhS 3-110 O H 4-MeOBz 4-HO-3,5-di- Me H 4-FBz 1 1 tBuPhO3-111 O H 2-BozPh 4-HO-3,5-di- Et H 4-FBz 1 1 tBuPhS 3-112 O H 2-BozPh4-HO-3,5-di- Pr H 4-FBz 1 1 tBuPhS 3-113 O H 2-BozPh 4-HO-3,5-di- iPr H4-FBz 1 1 tBuPhS 3-114 O H 2-BozPh 4-HO-3,5-di- Bu H 4-FBz 1 1 tBuPhS3-115 O H 2-BozPh 4-HO-3,5-di- iBu H 4-FBz 1 1 tBuPhS 3-116 O H 2-BozPh4-HO-3,5-di- sBu H 4-FBz 1 1 tBuPhS 3-117 O H 2-BozPh 4-HO-3,5-di- Pn H4-FBz 1 1 tBuPhS 3-118 O H 2-BozPh 4-HO-3,5-di- Hx H 4-FBz 1 1 tBuPhS3-119 O H 2-BozPh 4-HO-3,5-di- Ph H 4-FBz 1 1 tBuPhS 3-120 O H 2-BozPh4-HO-3,5-di- Bz H 4-FBz 1 1 tBuPhS 3-121 O H 2-BozPh 4-HO-3,5-di- Me Me4-FBz 1 1 tBuPhS 3-122 O H 2-BozPh 4-HO-3,5-di- Me Et 4-FBz 1 1 tBuPhS3-123 O H 2-BozPh 4-HO-3,5-di- Me Pr 4-FBz 1 1 tBuPhS 3-124 O H 2-I3ozPh4-HO-3,5-di- Me iPr 4-FBz 1 1 tBuPhS 3-125 O H 2-BozPh 4-HO-3,5-di- MeBu 4-FBz 1 1 tBuPhS 3-126 O H 2-BozPh 4-HO-3,5-di- Me iBu 4-FBz 1 1tBuPhS 3-127 O H 2-BozPh 4-HO-3,5-di- Me sBu 4-FBz 1 1 tBuPhS 3-128 O H2-BozPh 4-HO-3,5-di- Me Pn 4-FBz 1 1 tBuPhS 3-129 O H 2-BozPh4-HO-3,5-di- Me Hx 4-FBz 1 1 tBuPhS 3-130 O H 2-BozPh 4-HO-3,5-di- Me Ph4-FBz 1 1 tBuPhS 3-131 O H 2-BozPh 4-HO-3,5-di- Me 4-FPh 4-FBz 1 1tBuPhS 3-132 O H 2-BozPh 4-HO-3,5-di- Me 3-CF₃Ph 4-FBz 1 1 tBuPhS 3-133O H 2-BozPh 4-HO-3,5-di- Me 3-MeOPh 4-FBz 1 1 tBuPhS 3-134 O H 2-BozPh4-HO-3,5-di- Me 2-MePh 4-FBz 1 1 BuPhS 3-135 O H 2-BozPh 4-HO-3,5-di- Me4-CNPh 4-FBz 1 1 tBuPbS 3-136 O H 2-BozPh 4-HO-3,5-di- Me Bz 4-FBz 1 1BuPhS 3-137 O H 2-BozPh 4-HO-3,5-di- Me 3-FBz 4-FBz 1 1 tBuPbS 3-138 O H2-BozPh 4-HO-3,5-di- Me 2-CF₃Bz 4-FBz 1 1 tBuPhS 3-139 O H 2-BozPh4-HO-3,5-di- Me 3,5-diMeOBz 4-FBz 1 1 tBuPhS 3-140 O H 2-I3ozPh4-HO-3,5-di- Me 4-ClBz 4-FBz 1 1 tBuPhS 3-141 O Cl 2-BozPh 4-HO-3,5-di-Me H 4-FBz 1 1 tBuPhS 3-142 O F 2-BozPh 4-HO-3,5-di- Me H 4-FBz 1 1tBuPhS 3-143 O Br 2-BozPh 4-HO-3,5-di- Me 4-FBz 1 1 tBuPhS 3-144 O Me2-BoZPh 4-HO-3,5-di- Me 4-FBz 1 1 tBuPhS 3-145 O MeO 2-BozPh4-HO-3,5-di- Me 4-FBz 1 1 tBuPhS 3-146 O EtO 2-BozPh 4-HO-3,5-di- Me4-FBz 1 1 tBuPhS 3-147 O iPr 2-BozPh 4-HO-3,5-di- Me 4-FBz 1 1 tBuPhS3-148 O CF₃ Me 4-HO-3,5-di- Me 4-FBz 1 1 tBuPhS 3-149 O HO Me4-HO-3,5-di- Me 4-FBz 1 1 tBuPhS 3-150 O EtO Et 4-HO-3,5-di- Me 4-FBz 11 tBuPhS 3-151 O tBu Pr 4-HO-3,5-di- Me 4-FBz 1 1 tBuPhS 3-152 O Ac iPr4-HO-3,5-di- Me H 4-FBz 1 1 tBuPhS 3-153 O Boz Bu 4-HO-3,5-di- Me H4-FBz 1 1 tBuPhS 3-154 O PhAc iBu 4-HO-3,5-di- Me H 4-FBz 1 1 tBuPhS3-155 O cPnc sBu 4-HO-3,5-di- Me H 4-FBz 1 1 tBuPhS 3-156 O NH₂ tBu4-HO-3,5-di- Me H 4-FBz 1 1 tBuPhS 3-157 O NHAc Pn 4-HO-3,5-di- Me H4-FBz 1 1 tBuPhS 3-158 O NHBoz iPn 4-HO-3,5-di- Me H 4-FBz 1 1 tBuPhS3-159 O NHMe sPn 4-HO-3,5-di- Me H 4-FBz 1 1 tBuPhS 3-160 O NHiPr Hx4-HO-3,5-di- Me H 4-FBz 1 1 tBuPhS 3-161 O NHPh iHx 4-HO-3,5-di- Me H4-FBz 1 1 tBuPhS 3-162 O NHBz sHx 4-HO-3,5-di- Me H 4-FBz 1 1 tBuPhS3-163 O NMeEt Ph 4-HO-3,5-di- Me H 4-FBz 1 1 tBuPhS 3-164 O NEtPh 4-FPh4-HO-3,5-di- Me H 4-FBz 1 1 tBuPbS 3-165 O NPhBz 4-ClPh 4-HO-3,5-di- MeH 4-FBz 1 1 tBuPhS 3-166 O Ph 3-CF₃Ph 4-HO-3,5-di- Me H 4-FBz 1 1 tBuPhS3-167 O Np 2-MePh 4-HO-3,5-di- Me H 4-FBz 1 1 tBuPhS 3-168 O CN 3-MeOPh4-HO-3,5-di- Me H 4-FBz 1 1 tBuPhS 3-169 O NO₂ 2-FPh 4-HO-3,5-di- Me H4-FBz 1 1 tBuPhS 3-170 O H 3-ClBz 4-HO-2,3,5- Me H H 1 1 triMePhO 3-171O H 4-ClBz 4-HO-2,3,5- Me H Me 1 1 triMePhO 3-172 O H 2-FBz 4-HO-2,3,5-Me H Et 1 1 triMePhO 3-173 O H 3-FBz 4-HO-2,3,5- Me H Bu 1 1 triMePhO3-174 O H 4-FBz 4-HO-2,3,5- Me H Ph 1 1 triMePhO 3-175 O H 2-CF₃Bz4-HO-2,3,5- Me H Bz 1 1 triMePhO 3-176 O H 3-CF₃Bz 4-HO-2,3,5- Me H Bz 11 triMePhO 3-177 O H Me MeO Me H H 1 1 3-178 O H 3-MeBz MeO Me H Me 1 13-179 O H 4-MeBz MeO Me H Et 1 1 3-180 O H 2-MeOBz MeO Me H Pr 1 1 3-181O H 3-MeOBz MeO Me H iPr 1 1 3-182 O H 4-MeOBz MeO Me H Pn 1 1 3-183 O H4-BrBz MeO Me H Hx 1 1 3-184 O H 2-BozPh MeO Me H Bz 1 1 3-185 O H2-BozPh MeO Me H 4-FBz 1 1 3-186 O H 2-BozPh MeO Me H 3-ClBz 1 1 3-187 OH 2-BozPh MeO Me H Ph 1 1 3-188 O H 2-BozPh MeO Me H H 1 1 3-189 O H2-BozPh MeO Me H H 1 1 3-190 O H 2-Bozph MeO Me H H 1 1 3-191 O H2-BozPh EtO Me H Bz 1 1 3-192 O H 2-BozPh PrO Me H Bz 1 1 3-193 O H2-BozPh iPrO Me H Bz 1 1 3-194 O H 2-BozPh BuO Me H Bz 1 1 3-195 O H2-BozPh iBuO Me H Bz 1 1 3-196 O H 2-BozPh sBuO Me H Bz 1 1 3-197 O H2-BozPh tBuO Me H Bz 1 1 3-198 O H 2-BozPh PnO Me H Bz 1 1 3-199 O H2-BozPh HxO Me H Bz 1 1 3-200 O H 2-BozPh PhO Me H Bz 1 1 3-201 O H2-BozPh 4-ClPhO Me H Bz 1 1 3-202 O H 2-BozPh 4-FPhO Me H Bz 1 1 3-203 OH 2-BozPh 2-FPhO Me H Bz 1 1 3-204 O H 2-BozPh 3-FPhO Me H Bz 1 1 3-205O H 2-BozPh 4-CF₃PhO Me H Bz 1 1 3-206 O H 2-BozPh 3-CF₃PhO Me H Bz 1 13-207 O H 2-BozPh 4-MeOPhO Me H Bz 1 1 3-208 O H 2-BozPh 4-MePhO Me H Bz1 1 3-209 O H 2-BozPh 4-PhPhO Me H Bz 1 1 3-210 O H 2-BozPh 3-HOPhO Me HBz 1 1 3-211 O H 2-BozPh 3-AcPhO Me H Bz 1 1 3-212 O H 2-BozPh 4-cPrPhOMe H Bz 1 1 3-213 O H 2-BozPh 4-Me₂NPhO Me H Bz 1 1 3-214 O H 2-BozPh4-CNPhO Me H Bz 1 1 3-215 O H 2-BozPh 4-NO₂PhO Me H Bz 1 1 3-220 O H2-BozPh Ph Me H Bz 1 1 3-221 O H 2-BozPh Np Me H Bz 1 1 3-222 O H2-BozPh 4-MeOPh Me H Bz 1 1 3-223 O H 2-BozPh Bz Me H Bz 1 1 3-224 O H2-BozPh 4-CF₃Bz Me H Bz 1 1 3-225 O H 2-BozPh MeS Me H Bz 1 1 3-226 O H2-BozPh PbS Me H Bz 1 1 3-227 O H 2-BozPh BzS Me H Bz 1 1 3-228 O H Me4-FPhS Me H Bz 1 1 3-229 O H Me 4-CF₃PhS Me H Bz 1 1 3-230 O H Et 4-FBzSMe H Bz 1 1 3-231 O H Pr F Me H Bz 1 1 3-232 O H iPr Cl Me H Bz 1 13-233 O H Bu Br Me H Bz 1 1 3-234 O H iBu 2-PyrS Me H Bz 1 1 3-235 O HsBu 3-PyrS Me H 4-FBz 1 1 3-236 O H tBu 4-PyrS Me H 4-CF₃Bz 1 1 3-237 OH Pn 2-PyrO Me H 3-MeOBz 1 1 3-238 O H iPn 3-PyrO Me H Bz 1 1 3-239 O HsPn 4-PyrO Me H Bz 1 1 3-240 O H Hx cPrS Me H Bz 1 1 3-241 O H iHx cHxSH Bz 1 1 3-242 O H sHx NH₂ H Bz 1 1 3-243 O H Ph NHMe H Bz 1 1 3-244 O H4-FPh NMeEt H Bz 1 1 3-245 O H 4-ClPh NHAc H Bz 1 1 3-246 O H 3-CF₃PhNHPh H Bz 1 1 3-247 O H 2-MePh NHBz H Bz 1 1 3-248 O H 3-MeOPh NHBoz HBz 1 1 3-249 O H 2-FPh NMeBoz H Bz 1 1 3-250 O H Bz NEtBz H Bz 1 1 3-251O H 3-ClBz NPhBz H Bz 1 1 3-252 O H 2-ClBz NPhBoz H Bz 1 1 3-253 O H4-ClBz NH(4-FBoz) H Bz 1 1 3-254 O H 2-FBz NH(3- H Bz 1 1 MeOBoz) 3-255O H 3-FBz NHBoz Me Bz 1 1 3-256 O H 4-FBz NHBoz Et Bz 1 1 3-257 O H2-CF₃Bz NHBoz Ph Bz 1 1 3-258 O H 3-CF₃Bz NHBoz Bz Bz 1 1 3-259 O H Me4-AdaPhO H MeSO₂ 1 1 3-260 O H Me 4-HO-3,5-di- Me H MeSO₂ 1 1 tBuPhS3-261 O H Me MeO Me H MeSO₂ 1 1 3-262 O H Me 4-AdaPhO Me H Tos 1 1 3-263O H Me 4-HO-3,5-di- Me H Tos 1 1 tBuPhS 3-264 O H Me MeO Me H Tos 1 13-265 O H Me 4-AdaPhO Me H CF₃SO₂ 1 1 3-266 O H Me 4-HO-3,5-di- Me HCF₃SO₂ 1 1 tBuPhS 3-267 O H Me MeO Me H CF₃SO₂ 1 1 3-268 O H Me 4-AdaPhOMe H Bz 1 1 3-269 O H Me 4-HO-3,5-di- Me H Bz 1 1 tBuPhS 3-270 O H MeMeO Me H Bz 1 1 3-271 O H Me 4-AdaPhO Me H CF₃SO₂ 1 1 3-272 O H Me4-HO-3,5-di- Me H CF₃SO₂ 1 1 tBuPhS 3-273 O H Me MeO Me H CF₃SO₂ 1 13-274 O H 4-CF₃Bz 4-H₂N-3,5-di- Me H H 1 1 MePhO 3-275 O H 3-MeBz4-H₂N-3,5-di- Me H Me 1 1 MePhO 3-276 O H 4-MeBz 4-H₂N-3,5-di- Me H Et 11 MePhO 3-277 O H 2-MeOBz 4-H₂N-3,5-di- Me H Pr 1 1 MePhO 3-278 O H3-MeOBz 4-H₂N-3,5-di- Me H iPr 1 1 MePhO 3-279 O H 4-MeOBz 4-H₂N-3,5-di-Me H Pn 1 1 MePhO 3-280 O H 4-BrBz 4-H₂N-3,5-di- Me H Hx 1 1 MePhO 3-281O H 2-BozPh 4-H₂N-3,5-di- Me H Bz 1 1 MePhO 3-282 O H 2-BozPh4-H₂N-3,5-di- Me H 4-FBz 1 1 MePhO 3-283 O H 2-BozPh 4-H₂N-3,5-di- Me H3-ClBz 1 1 MePhO 3-284 O H 2-BozPh 4-H₂N-3,5-di- Me H Ph 1 1 MePhO 3-285O H 2-BozPh 4-H₂N-3,5-di- Me H H 1 1 MePhO 3-286 O H 2-BozPh4-H₂N-3,5-di- Me H H 1 1 MePhO 3-287 O H 2-BozPh 4-H₂N-3,5-di- Me H H 11 MePhO 3-288 O H 4-CF₃Bz 4-(4- Me H H 1 1 CF₃PhCarNH)- 3,5-di-MePhO3-289 O H 3-MeBz 4-(4- Me H Me 1 1 CF₃PhCarNH)- 3,5-di-MePhO 3-290 O H4-MeBz 4-(4- Me H Et 1 1 CF₃PhCarNH)- 3,5-di-MePhO 3-291 O H 2-MeOBz4-(4- Me H Pr 1 1 CF₃PhCarNH)- 3,5-di-MePhO 3-292 O H 3-MeOBz 4-(4- Me HiPr 1 1 CF₃PhCarNH)- 3,5-di-MePhO 3-293 O H 4-MeOBz 4-(4- Me H Pn 1 1CF₃PhCarNH)- 3,5-di-MePhO 3-294 O H 2-BrBz 4-(4- Me H Hx 1 1CF₃PhCarNH)- 3,5-di-MePhO 3-295 O H 2-BozPh 4-(4- Me H Bz 1 1CF₃PhCarNH)- 3,5-di-MePhO 3-296 O H 2-BozPh 4-(4- Me H 4-FBz 1 1CF₃PhCarNH)- 3,5-di-MePhO 3-297 O H 2-BozPh 4-(4- Me H 3-ClBz 1 1CF₃PhCarNH)- 3,5-di-MePhO 3-298 O H 2-BozPh 4-(4- Me H Ph 1 1CF₃PhCarNH)- 3,5-di-MePhO 3-299 O H 2-BozPh 4-(4- Me H H 1 1CF₃PhCarNH)- 3,5-di-MePhO 3-300 O H 3-BozPh 4-(4- Me H H 1 1CF₃PhCarNH)- 3,5-di-MePhO 3-301 O H 4-BozPh 4-(4- Me H H 1 1CF₃PhCarNH)- 3,5-di-MePhO

[0368] TABLE 4 (I-4)

(Wherein R₁, R₂, R₃, R₄, A, B, W₁, W₂, X, Y, Z₄, m and n are as definedabove.) E.C. No. B X R₄ Z₄ R₁ R₂ R₃ m n 4-1 O H 3-ClBz 4-AdaPhO Me H4-FBz 1 1 4-2 O H 3-ClBz 4-AdaPhO Me H 4-FBz 1 0 4-3 O H 3-ClBz 4-AdaPhOMe H 4-FBz 1 2 4-4 O H 3-ClBz 4-AdaPhO Me H 4-FBz 1 3 4-5 O H 3-ClBz4-AdaPhO Me H 4-FBz 1 4 4-6 O H 3-ClBz 4-AdaPhO Me H 4-FBz 1 5 4-7 O H3-ClBz 4-AdaPhO Me H 4-FBz 1 6 4-8 O H 3-ClBz 4-AdaPhO Me H 4-FBz 1 74-9 O H 3-ClBz 4-AdaPhO Me H 4-FBz 1 8 4-10 O H 3-ClBz 4-AdaPhO Me H4-FBz 2 1 4-11 O H 3-ClBz 4-AdaPhO Me H 4-FBz 3 1 4-12 O H 3-ClBz4-AdaPhO Me H 4-FBz 4 1 4-13 O H 3-ClBz 4-AdaPhO Me H 4-FBz 5 1 4-14 O H3-ClBz 4-AdaPhO Me H 4-FBz 6 1 4-15 O H 3-ClBz 4-AdaPhO Me H 4-FBz 7 14-16 O H 3-ClBz 4-AdaPhO Me H 4-FBz 8 1 4-17 O NPhBz sPn 4-AdaPhO Me H4-FBz 1 1 4-18 O NPhBz sPn 4-AdaPhO Me H 4-FBz 1 0 4-19 O NPhBz sPn4-AdaPhO Me H 4-FBz 1 2 4-20 O NPhBz sPn 4-AdaPhO Me H 4-FBz 1 3 4-21 ONPhBz sPn 4-AdaPhO Me H 4-FBz 1 4 4-22 O NPhBz sPn 4-AdaPhO Me H 4-FBz 15 4-23 O NPhBz sPn 4-AdaPhO Me H 4-FBz 1 6 4-24 O NPhBz sPn 4-AdaPhO MeH 4-FBz 1 7 4-25 O NPhBz sPn 4-AdaPhO Me H 4-FBz 1 8 4-26 O NPhBz sPn4-AdaPhO Me H 4-FBz 2 1 4-27 O NPhBz sPn 4-AdaPhO Me H 4-FBz 3 1 4-28 ONPhBz sPn 4-AdaPhO Me H 4-FBz 4 1 4-29 O NPhBz sPn 4-AdaPhO Me H 4-FBz 51 4-30 O NPhBz sPn 4-AdaPhO Me H 4-FBz 6 1 4-31 O NPhBz sPn 4-AdaPhO MeH 4-FBz 7 1 4-32 O NPhBz sPn 4-AdaPhO Me H 4-FBz 8 1 4-33 O H 4-MeBz4-HO-3,5-di-tBuPhS Me H 4-FBz 1 1 4-34 O H 4-MeBz 4-HO-3,5-di-tBuPhS MeH 4-FBz 1 0 4-35 O H 4-MeBz 4-HO-3,5-di-tBuPhS Me H 4-FBz 1 2 4-36 O H4-MeBz 4-HO-3,5-di-tBuPhS Me H 4-FBz 1 3 4-37 O H 4-MeBz4-HO-3,5-di-tBuPhS Me H 4-FBz 1 4 4-38 O H 4-MeBz 4-HO-3,5-di-tBuPhS MeH 4-FBz 1 5 4-39 O H 4-MeBz 4-HO-3,5-di-tBuPhS Me H 4-FBz 1 6 4-40 O H4-MeBz 4-HO-3,5-di-tBuPhS Me H 4-FBz 1 7 4-41 O H 4-MeBz4-HO-3,5-di-tBuPhS Me H 4-FBz 1 8 4-42 O H 4-MeBz 4-HO-3,5-di-tBuPhS MeH 4-FBz 2 1 4-43 O H 4-MeBz 4-HO-3,5-di-tBuPhS Me H 4-FBz 3 1 4-44 O H4-MeBz 4-HO-3,5-di-tBuPhS Me H 4-FBz 4 1 4-45 O H 4-MeBz4-HO-3,5-di-tBuPhS Me H 4-FBz 5 1 4-46 O H 4-MeBz 4-HO-3,5-di-tBuPhS MeH 4-FBz 6 1 4-47 O H 4-MeBz 4-HO-3,5-di-tBuPhS Me H 4-FBz 7 1 4-48 O H4-MeBz 4-HO-3,5-di-tBuPhS Me H 4-FBz 8 1 4-49 O NPhBz Bz4-HO-3,5-di-tBuPhS Me H 4-FBz 1 1 4-50 O NPhBz Bz 4-HO-3,5-di-tBuPbS MeH 4-FBz 1 0 4-51 O NPhBz Bz 4-HO-3,5-di-tBuPhS Me H 4-FBz 1 2 4-52 ONPhBz Bz 4-HO-3,5-di-tBuPhS Me H 4-FBz 1 3 4-53 O NPhBz Bz4-HO-3,5-di-tBuPhS Me H 4-FBz 1 4 4-54 O NPhBz Bz 4-HO-3,5-di-tBuPhS MeH 4-FBz 1 5 4-55 O NPhBz Bz 4-HO-3,5-di-tBuPhS Me H 4-FBz 1 6 4-56 ONPhBz Bz 4-HO-3,5-di-tBuPhS Me H 4-FBz 1 7 4-57 O NPhBz Bz4-HO-3,5-di-tBuPhS Me H 4-FBz 1 8 4-58 O NPhBz Bz 4-HO-3,5-di-tBuPhS MeH 4-FBz 2 1 4-59 O NPhBz Bz 4-HO-3,5-di-tBuPhS Me H 4-FBz 3 1 4-60 ONPhBz Bz 4-HO-3,5-di-tBuPhS Me H 4-FBz 4 1 4-61 O NPhBz Bz4-HO-3,5-di-tBuPhS Me H 4-FBz 5 1 4-62 O NPhBz Bz 4-HO-3,5-di-tBuPhS MeH 4-FBz 6 1 4-63 O NPhBz Bz 4-HO-3,5-di-tBuPhS Me H 4-FBz 7 1 4-64 ONPhBz Bz 4-HO-3,5-di-tBuPhS Me H 4-FBz 8 1

[0369] TABLE 5 (I-5)

(Wherein R₁, R₂, R₃, A, B, W₁, W₂, X, Y, Z₁, m and n are as definedabove.) E.C. No. B X Y Z₁ R₁ R₂ R₃ m n 5-1 O H S MeO Me H H 1 1 5-2 O HSO MeO Me H H 1 1 5-3 O H SO₂ MeO Me H H 1 1 5-4 O H S MeO Me H Me 1 15-5 O H S MeO Me H Me 1 0 5-6 O H S MeO Me H Me 1 2 5-7 O H S MeO Me HMe 1 3 5-8 O H S MeO Me H Me 1 4 5-9 O H S MeO Me H Me 1 5 5-10 O H SMeO Me H Me 1 6 5-11 O H S MeO Me H Me 1 7 5-12 O H S MeO Me H Me 1 85-13 O H S MeO Me H Me 2 1 5-14 O H S MeO Me H Me 3 1 5-15 O H S MeO MeH Me 4 1 5-16 O H S MeO Me H Me 5 1 5-17 O H S MeO Me H Me 6 1 5-18 O HS MeO Me H Me 7 1 5-19 O H S MeO Me H Me 8 1 5-20 O H S MeO Me H Me 2 25-21 O H SO MeO Me H Me 1 1 5-22 O H SO₂ MeO Me H Me 1 1 5-23 O H S HOMe H H 1 1 5-24 O H SO HO Me H H 1 1 5-25 O H SO₂ HO Me H H 1 1 5-26 O HS HO Me H Me 1 1 5-27 O H S HO Me H Me 1 0 5-28 O H S HO Me H Me 1 25-29 O H S HO Me H Me 1 3 5-30 O H S HO Me H Me 1 4 5-31 O H S HO Me HMe 1 5 5-32 O H S HO Me H Me 1 6 5-33 O H S HO Me H Me 1 7 5-34 O H S HOMe H Me 1 8 5-35 O H S HO Me H Me 2 1 5-36 O H S HO Me H Me 3 1 5-37 O HS HO Me H Me 4 1 5-38 O H S HO Me H Me 5 1 5-39 O H S HO Me H Me 6 15-40 O H S HO Me H Me 7 1 5-41 O H S HO Me H Me 8 1 5-42 O H S HO Me HMe 2 2 5-43 O H SO HO Me H Me 1 1 5-44 O H SO₂ HO Me H Me 1 1 5-45 O H SGlcA Me H H 1 1 5-46 O H SO GlcA Me H H 1 1 5-47 O H SO₂ GlcA Me H H 1 15-48 O H S GlcA Me H Me 1 1 5-49 O H S GlcA Me H Me 1 0 5-50 O H S GlcAMe H Me 1 2 5-51 O H S GlcA Me H Me 1 3 5-52 O H S GlcA Me H Me 1 4 5-53O H S GlcA Me H Me 1 5 5-54 O H S GlcA Me H Me 1 6 5-55 O H S GlcA Me HMe 1 7 5-56 O H S GlcA Me H Me 1 8 5-57 O H S GlcA Me H Me 2 1 5-58 O HS GlcA Me H Me 3 1 5-59 O H S GlcA Me H Me 4 1 5-60 O H S GlcA Me H Me 51 5-61 O H S GlcA Me H Me 6 1 5-62 O H S GlcA Me H Me 7 1 5-63 O H SGlcA Me H Me 8 1 5-64 O H S GlcA Me H Me 2 2 5-65 O H SO GlcA Me H Me 11 5-66 O H SO₂ GlcA Me H Me 1 1 5-67 O H S MeS Me H Me 1 1 5-68 O H SMeS Me H H 1 1

[0370] The table above may preferably include the followingexemplification compound Nos.:

[0371] 1-1)3-[4-[6-(4-adamantan-1-ylphenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]phenyl]-2-(4-fluorobenzyloxy)propionicacid,

[0372] 1-86)3-[4-[6-(3,5-di-t-butyl-4-hydroxyphenylthio)-1-methyl-1H-benzimidazol-2-ylmethoxy]phenyl]-2-(4-fluorobenzyloxy)propionicacid,

[0373] 1-87)4-[6-(3,5-di-t-butyl-4-hydroxyphenylthio)-1-methyl-1H-benzimidazol-2-ylmethoxy]phenyllacticacid,

[0374] 1-170)4-[6-(4-hydroxy-2,3,5-trimethylphenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]phenyllacticacid,

[0375] 1-177)4-(1-methyl-6-methoxy-1H-benzimidazol-2-ylmethoxy)phenyllactic acid,

[0376] 1-179)2-ethoxy-3-[4-(1-methyl-6-methoxy-1H-benzimidazol-2-ylmethoxy)phenyl]propionicacid,

[0377] 3-188)N-(2-benzoylphenyl)-4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenylalanine,

[0378] 3-285)4-[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]-N-(2-benzoylphenyl)phenylalanine,

[0379] 3-299)4-[6-[4-(4-trifluoromethylphenylureide)-3,5-dimethylphenoxy]-1-methyl-1H-benzimidazol-2-ylmethoxy]-N-(2-benzoylphenyl)phenylalanine,

[0380] 5-1)3-[4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]-2-mercaptopropionicacid,

[0381] 5-4)3-[4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylthiopropionicacid,

[0382] 5-21)3-[4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylsulfenylpropionicacid,

[0383] 5-22)3-[4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylsulfonylpropionicacid,

[0384] 5-23)3-[4-(6-hydroxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]-2-mercaptopropionicacid,

[0385] 5-26)3-[4-(6-hydroxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylthiopropionicacid,

[0386] 5-43)3-[4-(6-hydroxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylsulfenylpropionicacid,

[0387] 5-45) 3-[4-[6-(β-D-glucopyranosyloxyuronicacid)-1-methyl-1H-benzimidazol-2-ylmethoxy]phenyl]-2-mercaptopropionicacid,

[0388] 5-48) 3-[4-[6-(β-D-glucopyranosyloxyuronicacid)-1-methyl-1H-benzimidazol-2-ylmethoxy]phenyl]-2-methylthiopropionicacid,

[0389] 5-65) 3-[4-[6-(β-D-glucopyranosyloxyuronicacid)-1-methyl-1H-benzimidazol-2-ylmethoxy]phenyl]-2-methylsulfenylpropionicacid,

[0390] 5-67)3-[4-(1-methyl-6-methylthio-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylthiopropionicacid,

[0391] 5-68)3-[4-(1-methyl-6-methylthio-1H-benzimidazol-2-ylmethoxy)phenyl]-2-mercaptopropionicacid,

[0392] pharmacologically acceptable esters or amides thereof, orpharmacologically acceptable salts thereof.

[0393] More preferable are:

[0394] 1-1)3-[4-[6-(4-adamantan-1-ylphenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]phenyl]-2-(4-fluorobenzyloxy)propionicacid,

[0395] 1-86)3-[4-[6-(3,5-di-t-butyl-4-hydroxyphenylthio)-1-methyl-1H-benzimidazol-2-ylmethoxy]phenyl]-2-(4-fluorobenzyloxy)propionicacid,

[0396] 1-87)4-[6-(3,5-di-t-butyl-4-hydroxyphenylthio)-1-methyl-1H-benzimidazol-2-ylmethoxy]phenyllacticacid,

[0397] 1-170)4-[6-(4-hydroxy-2,3,5-trimethylphenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]phenyllacticacid,

[0398] 1-177)4-(1-methyl-6-methoxy-1H-benzimidazol-2-ylmethoxy)phenyllactic acid,

[0399] 1-179)2-ethoxy-3-[4-(1-methyl-6-methoxy-1H-benzimidazol-2-ylmethoxy)phenyl]propionicacid,

[0400] 3-188)N-(2-benzoylphenyl)-4(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenylalanine,

[0401] 3-285)4-[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]-N-(2-benzoylphenyl)phenylalanine,

[0402] 3-299)4-[6-[4-(4trifluoromethylphenylureide)-3,5-dimethylphenoxy]-1-methyl-1H-benzimidazol-2-ylmethoxy]-N-(2-benzoylphenyl)phenylalanine,

[0403] 5-1)3-[4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]-2-mercaptopropionicacid,

[0404] 5-4)3-[4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylthiopropionicacid,

[0405] 5-21)3-[4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylsulfenylpropionicacid,

[0406] 5-22)3-[4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylsulfonylpropionicacid,

[0407] 5-26)3-[4-(6-hydroxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylthiopropionicacid,

[0408] 5-48) 3-[4-[6-(β-D-glucopyranosyloxyuronicacid)-1-methyl-1H-benzimidazol-2-ylmethoxy]phenyl]-2-methylthiopropionicacid,

[0409] 5-67)3-[4-(1-methyl-6-methylthio-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylthiopropionicacid,

[0410] 5-68)3-[4-(1-methyl-6-methylthio-1H-benzimidazol-2-ylmethoxy)phenyl]-2-mercaptopropionicacid,

[0411] pharmacologically acceptable esters or amides thereof, orpharmacologically acceptable salts thereof

[0412] Most preferable are:

[0413] 1-1)3-[4-[6-(4-adamantan-1-ylphenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]phenyl]-2-(4-fluorobenzyloxy)propionicacid,

[0414] 1-86)3-[4-[6-(3,5-di-t-butyl-4-hydroxyphenylthio)-1-methyl-1H-benzimidazol-2-ylmethoxy]phenyl]-2-(4-fluorobenzyloxy)propionicacid,

[0415] 1-179)2-ethoxy-3-[4-(1-methyl-6-methoxy-1H-benzimidazol-2-ylmethoxy)phenyl]propionicacid,

[0416] 3-188)N-(2-benzoylphenyl)-4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenylalanine,

[0417] 3-285)4-[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]-N-(2-benzoylphenyl)phenylalanine,

[0418] 5-21)3-[4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylsulfenylpropionicacid,

[0419] 5-67)3-[4-(1-methyl-6-methylthio-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylthiopropionicacid,

[0420] pharmacologically acceptable esters or amides thereof, orpharmacologically acceptable salts thereof.

[0421] Compounds having formula (I) of the present invention can beprepared according to the following processes A-S:

[0422] Process A:

[0423] wherein

[0424] R₁, R₂, R₃, W₁, W₂, X, Y, A and B independently represent asdefined above, Z represents Z₁, Z₂O-group, Z₃S-group or Z₄ as describedabove, Y′ represents Y or N—R₄-group as described above (where R₄represents as defined above), and R represents an ester residue asdescribed above.

[0425] In Process A, compound (V) can be allowed to react with water inan inert solvent in the presence of an acid or base to prepare compoundshaving general formulae (I)-(IV).

[0426] Any inert solvent can be used in the reaction above as long as itis inert in the reaction. Such inert solvents include, but are notlimited to, for example: aliphatic hydrocarbons such as hexane, heptane,ligroin or petroleum ether; aromatic hydrocarbons such as benzene,toluene or xylene; halogenated hydrocarbons such as chloroform,dichloromethane, 1,2-dichloroethane or carbon tetrachloride; ethers suchas diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane,dimethoxyethane or di(ethylene glycol) dimethyl ether; amides such asdimethylformamide, dimethylacetamide or hexamethylphosphoric triamide;alcohols such as methanol, ethanol or propanol; water; and mixturesthereof. Ethers, alcohols, amides, water and mixtures thereof arepreferable, and alcohols and ethers are more preferable. Particularly,toluene and tetrahydrofuran are preferable.

[0427] Any acid which can be used as an acid catalyst in conventionalreactions may be used in the above-described reaction. Such acidsinclude, but are not limited to, for example: inorganic acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid orphosphoric acid; Bronsted acids including organic acids such as aceticacid, formic acid, oxalic acid, methanesulfonic acid, p-toluenesulfonicacid, camphorsulfonic acid, trifluoroacetic acid ortrifluoromethanesulfonic acid; Lewis acids such as zinc chloride, tintetrachloride, boron trichloride, boron trifluoride or boron tribromide;and acidic ion-exchange resins. Inorganic and organic acids(particularly hydrochloric acid, acetic acid or trifluoroacetic acid)are preferable.

[0428] Any base which will not have any effect on any other moietiesthan the target moiety in the compound may be used in theabove-described reaction. Such bases include, but are not limited to,for example: alkali metal carbonates such as lithium carbonate, sodiumcarbonate or potassium carbonate; alkali metal bicarbonates such aslithium bicarbonate, sodium bicarbonate or potassium bicarbonate; alkalimetal hydroxides such as lithium hydroxide, sodium hydroxide orpotassium hydroxide; metal alkoxides such as lithium methoxide, sodiummethoxide, sodium ethoxide or potassium-t-butoxide; and ammonia such asaqueous ammonia solution or concentrated ammonia-methanol. Alkali metalhydroxides and metal alkoxides (particularly, alkali metal hydroxidesand metal alkoxides) are preferable.

[0429] The reaction may typically be performed at from −20° C. to 150°C., and preferably at from 0° C. to 60° C. though the temperature maydepend on the starting material compounds, solvents and/or otherconditions to be used.

[0430] The reaction may typically be carried out for from 30 minutes to5 days, and preferably from 5 to 72 hours though the reaction time maydepend on the starting material compounds, solvents, reactiontemperature and/or other conditions to be used.

[0431] In this process, when R represents a benzyl group which may besubstituted, then compound (V) can be subjected to a catalytic reductionprocess in inert solvent under atmospheric or higher pressure(preferably under pressure higher than atmospheric) to produce targetcompounds (I)-(IV).

[0432] Any catalyst which can be used in conventional catalyticreduction processes may be used in the above-described catalyticreduction process. Such catalysts include, but are not limited to, forexample, palladium-carbon, Raney Nickel, rhodium-aluminum oxide,triphenylphosphine-rhodium oxide, palladium-barium sulfate, palladiumblack, platinum oxide and platinum black. Palladium-carbon ispreferable.

[0433] Any inert solvent can be used in the catalytic reduction processabove as long as it is inert in the reaction. Such inert solventsinclude, but are not limited to, for example: aliphatic hydrocarbonssuch as hexane, heptane, ligroin or petroleum ether; aromatichydrocarbons such as benzene, toluene or xylene; halogenatedhydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane orcarbon tetrachloride; ethers such as diethyl ether, diisopropyl ether,tetrahydrofuran, dioxane, dimethoxyethane or di(ethylene glycol)dimethyl ether; alcohols such as methanol, ethanol, n-propanol,isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol,di(ethylene glycol), glycerin, octanol, cyclohexanol or methylcellosolve; amides such as formamide, dimethylformamide,dimethylacetamide or hexamethylphosphoric triamide; organic acids suchas acetic acid or trifluoroacetic acid; and mixtures thereof. Ethers,alcohols and organic acids are preferable, and alcohols are morepreferable.

[0434] The reaction may typically be performed at from 0° C. to 100° C.,and preferably at from 10° C. to 50° C. though the temperature maydepend on the starting material compounds, catalysts, solvents and/orother conditions to be used.

[0435] The reaction may typically be carried out for from 30 minutes to48 hours though the reaction time may depend on the starting materialcompounds, catalysts, solvents, reaction temperature and/or otherconditions to be used.

[0436] Process B

[0437] wherein

[0438] R₁, R₂, R₃, W₁, W₂, X, Y′, Z, A, B and R independently representas defined above, and Boc group represents t-butoxycarbonyl group.

[0439] Process B, which is a process for preparing compounds of generalformula (V), can be carried out by allowing compound (VI) to react withcompound (VII) and then treating the reaction product with an acid. Inother words, in this process, the t-butoxycarbonyl group (the aminoprotecting group) may be removed by treatment with an acid as in theabove-described reaction without purifying the amide compound (theintermediate product), and a ring is then formed.

[0440] Alternatively, the present process can also be performed bypurifying the intermediate product (VIII) obtained by reaction ofcompound (VI) with compound (VII) (step B1), and then allowing theintermediate product (VIII) to be contacted with an acid (step B2).

[0441] Step B1 can be performed according to any of the followingprocesses (a)-(c).

[0442] (a) Acid Halide Process

[0443] An acid halide process may be performed by allowing compound(VII) to react with a halogenation agent (e.g., thionyl chloride,thionyl bromide, oxalic chloride, oxalic dichloride, phosphorusoxychloride, phosphorus trichloride or phosphorus pentachloride) in aninert solvent to obtain an acid halide, and allowing the acid halide toreact with compound (VI) or an acidified salt thereof in an inertsolvent in the presence or absence (preferably in the presence) of abase(s).

[0444] Bases which may be used in the above-described reaction include,for example: alkali metal carbonates such as lithium carbonate, sodiumcarbonate or potassium carbonate; alkali metal bicarbonates such aslithium bicarbonate, sodium bicarbonate or potassium bicarbonate; alkalimetal hydrides such as lithium hydride, sodium hydride or potassiumhydride; alkali metal hydroxides such as lithium hydroxide, sodiumhydroxide or potassium hydroxide; alkali metal alkoxides such as lithiummethoxide, sodium methoxide, sodium ethoxide or potassium t-butoxide;and organic amines such as triethylamine, tributylamine,diisopropylethylamine, N-methylmorpholine, pyridine,4-(N,N-dimethylamino)pyridine, N,N-dimethylaniline, N,N-diethylaniline,1,5-diazabicyclo[4.3.0]nona-5-ene, 1,4-diazabicyclo[2.2.2]octane (DABCO)or 1,8-diazabicyclo[5.4.0]-7-undecene (DBU). Organic amines(particularly, triethylamine) are preferable.

[0445] Any inert solvent can be used in the above-described reaction aslong as it is inert in the reaction. Such inert solvents include, butare not limited to, for example: aliphatic hydrocarbons such as hexane,heptane, ligroin or petroleum ether; aromatic hydrocarbons such asbenzene, toluene or xylene; halogenated hydrocarbons such asdichloromethane, chloroform, 1,2-dichloroethane or carbon tetrachloride;ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran,dioxane, dimethoxyethane or di(ethylene glycol) dimethyl ether; ketonessuch as acetone; amides such as formamide, dimethylformamide,dimethylacetamide or hexamethylphosphoric triamide; sulfoxides such asdimethyl sulfoxide; and sulfolane. Halogenated hydrocarbons, ethers andamides particularly dichloromethane, chloroform, tetrahydrofuran anddimethylformamide) are preferable.

[0446] The reaction temperature may depend on the starting materialcompounds, agents and/or other conditions to be used though the reactionof the halogenation agent with compound (VII) as well as the reaction ofthe acid halide with compound (VI) or acidified salt thereof maytypically be performed at from −20° C. to 150° C. Preferably, thereaction of the halogenation agent with compound (VII) may be performedat from −10° C. to 100° C. while the reaction of the acid halide withcompound (VI) or an acidified salt thereof may be performed at from −20°C. to 100° C.

[0447] The reaction time may depend on the starting material compounds,agents, reaction temperature and/or other conditions to be used thoughthe reaction of halogenation agent with compound (VII) as well as thereaction of the acid halide with compound (VI) or an acidified saltthereof may typically be performed for from 30 minutes to 80 hours, andpreferably from 1 to 48 hours.

[0448] (b) Active Ester Process

[0449] An active ester process may be performed by allowing compound(VII) to react with an active esterification agent to prepare an activeester which is then allowed to react with compound (VI) or an acidifiedsalt thereof in an inert solvent in the presence or absence (preferablyin the presence) of a base.

[0450] The active ester process can be preferably performed in thepresence of a condensation agent including, for example: N-hydroxycompounds such as N-hydroxysuccinimide, 1-hydroxybenzotriazole orN-hydroxy-5-norbornene-2,3-dicarboxyimide; disulfide compounds such asdipyridyldisulfide; carbodiimide compounds such asdicyclohexylcarbodiimide; carbonyldiimidazole; and triphenylphosphine.

[0451] Any inert solvent can be used in the above-described reaction aslong as it is inert in the reaction. Such inert solvents include, butare not limited to, for example: aliphatic hydrocarbons such as hexane,heptane, ligroin or petroleum ether; aromatic hydrocarbons such asbenzene, toluene or xylene; halogenated hydrocarbons such asdichloromethane, 1,2-dichloroethane or carbon tetrachloride; ethers suchas diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane,dimethoxyethane or di(ethylene glycol) dimethyl ether; ketones such asacetone; amides such as formamide, dimethylformamide, dimethylacetamideor hexamethylphosphoric triamide; sulfoxides such as dimethyl sulfoxide;and sulfolane. Ethers and amides (particularly dioxane, tetrahydrofuranand dimethylformamide) are preferable.

[0452] Bases which can be used in the above-described reaction include,for example, those which can be used for the acid halide processdescribed above.

[0453] The reaction temperature may depend on the starting materialcompounds, agents and/or other conditions to be used though the activeesterification process may be performed at from −70° C. to 150° C., andpreferably at from −10° C. to 100° C. while the reaction of the activeester with compound (VI) or an acidified salt thereof may be performedat from −20° C. to 100° C., and preferably at from 0° C. to 50° C.

[0454] The reaction time may depend on the starting material compounds,agents, reaction temperature and/or other conditions to be used thoughthe active esterification reaction as well as the reaction of the activeester with compound (VI) or acidified salt thereof may typically beperformed for from 30 minutes to 80 hours, and preferably from 1 to 48hours.

[0455] (c) Mixed Acid Anhydride Process

[0456] A mixed acid anhydride process may be performed by allowingcompound (VII) to react with a mixed acid anhydration agent in an inertsolvent in the presence or absence (preferably in the presence) of abase to prepare a mixed acid anhydride which is then allowed to reactwith compound (VI) or an acidified salt thereof in an inert solvent.

[0457] Bases which may be used in the above-described reaction include,for example: alkali metal carbonates such as lithium carbonate, sodiumcarbonate or potassium carbonate; alkali metal bicarbonates such aslithium bicarbonate, sodium bicarbonate or potassium bicarbonate; alkalimetal hydrides such as lithium hydride, sodium hydride or potassiumhydride; alkali metal hydroxides such as lithium hydroxide, sodiumhydroxide or potassium hydroxide; alkali metal alkoxides such as lithiummethoxide, sodium methoxide, sodium ethoxide or potassium t-butoxide;and organic amines such as triethylamine, tributylamine,diisopropylethylamine, N-methylmorpholine, pyridine,4-(N,N-dimethylamino)pyridine, N,N-dimethylaniline, N,N-diethylaniline,1,5-diazabicyclo[4.3.0]nona-5-ene, 1,4-diazabicyclo[2.2.2]-octane(DABCO) or 1,8-diazabicyclo[5.4.0]-7-undecene (DBU). Organic amines(particularly, triethylamine) are preferable.

[0458] Mixed acid anhydration agents which can be used in theabove-described reaction include, for example: C₁-C₄ alkyl halidecarbonates such as chloroethyl carbonate or chloroisobutyl carbonate;C₁-C₅ alkanoyl halides such as pivaloyl chloride; and di-C₁-C₄ alkyl ordi-C₆-C₁₄ aryl cyanophosphates such as cyanodiethyl phosphonate orcyanodiphenyl phosphonate. Di-C₁-C₄ alkyl and di-C₆-C₁₄ arylcyanophosphates (particularly cyanodiethyl phosphonate) are preferable.

[0459] Any inert solvent can be used in the above-described reaction forpreparing the mixed acid anhydride as long as it will not inhibit thereaction and may dissolve the starting materials to some extent. Suchinert solvents include, but are not limited to, for example: aliphatichydrocarbons such as hexane, heptane, ligroin or petroleum ether;aromatic hydrocarbons such as benzene, toluene or xylene; halogenatedhydrocarbons such as dichloromethane, 1,2-dichloroethane or carbontetrachloride; ethers such as diethyl ether, diisopropyl ether,tetrahydrofuran, dioxane, dimethoxyethane or di(ethylene glycol)dimethyl ether; ketones such as acetone; amides such as formamide,dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide;sulfoxides such as dimethyl sulfoxide; and sulfolane. Ethers and amides(particularly tetrahydrofuran and dimethylformamide) are preferable.

[0460] The reaction temperature for preparing mixed acid anhydrides maydepend on the starting material compounds, agents and/or otherconditions to be used though the reaction may typically be performed atfrom −50° C. to 100° C., and preferably from 0° C. to 60° C.

[0461] The reaction time for preparing the mixed acid anhydride maydepend on the starting material compounds, agents, reaction temperatureand/or other conditions to be used though it may typically be from 30minutes to 72 hours, and preferably from 1 to 24 hours.

[0462] The reaction of the mixed acid anhydride with compound (VI) or anacidified salt thereof may be performed in an inert solvent in thepresence or absence (preferably in the presence) of a base. The samebases and inert solvents as those which can be used in theabove-described process for preparing the mixed acid anhydride may alsobe used in this reaction.

[0463] The temperature for reaction of the mixed acid anhydride withcompound (VI) or acidified salt thereof may depend on the startingmaterial compounds, agents and/or other conditions to be used though itmay typically be from −30° C. to 100° C., and preferably from 0° C. to80° C.

[0464] The reaction of the mixed acid anhydride with compound (VI) or anacidified salt thereof may typically be performed for from 5 minutes to24 hours, and preferably from 30 minutes to 16 hours, though the timemay depend on the starting material compounds, agents, reactiontemperature and/or other conditions to be used.

[0465] In this reaction, compound (VI) can be reacted directly withcompound (VII) in the presence of a base when a di-C₁-C₄ alkylcyanophosphate or a di-C₆-C₁₄ aryl cyanophosphate is used.

[0466] After reaction is completed, the target compound (VIII) obtainedin this step may be isolated from the reaction mixture according to anyconventional method. For example, the reaction product may appropriatelybe neutralized; impurities, if any, may be removed by filtration; thenan organic solvent comprising two or more liquids which are not misciblewith each other (such as water and ethyl acetate) may be added; theorganic phase containing the target compound may be separated, washedwith, for example, water, and dried on, for example, magnesium sulfateanhydride, sodium sulfate anhydride, or sodium hydrogen carbonateanhydride; and the solvent may be then removed by distillation.

[0467] Step B2 (ring closure using an acid) may be performed by allowingcompound (VIII) to react in an inert solvent in the presence of an acid.

[0468] Any acid which can be used as an acid catalyst in conventionalreactions may be used in this step. Such acids include, but are notlimited to, for example: inorganic acids such as hydrochloric acid,hydrobromic acid, sulfuric acid, perchloric acid or phosphoric acid;Bronsted acids including organic acids such as acetic acid, formic acid,oxalic acid, methanesulfonic acid, p-toluenesulfonic acid,camphorsulfonic acid, trifluoroacetic acid or trifluoromethanesulfonicacid; Lewis acids such as zinc chloride, tin tetrachloride, borontrichloride, boron trifluoride or boron tribromide; and acidicion-exchange resins. Inorganic and organic acids (particularlyhydrochloric acid, acetic acid and trifluoroacetic acid) are preferable.

[0469] Any inert solvent can be used in this step as long as it is inertin the reaction. Such inert solvents include, but are not limited to,for example: aliphatic hydrocarbons such as hexane, heptane, ligroin orpetroleum ether; aromatic hydrocarbons such as benzene, toluene orxylene; halogenated hydrocarbons such as chloroform, dichloromethane,1,2-dichloroethane or carbon tetrachloride; esters such as methylacetate, ethyl acetate, propyl acetate, butyl acetate or diethylcarbonate; ethers such as diethyl ether, diisopropyl ether,tetrahydrofuran, dioxane, dimethoxyethane or di(ethylene glycol)dimethyl ether; alcohols such as methanol, ethanol, n-propanol,isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol,di(ethylene glycol), glycerin, octanol, cyclohexanol or methylcellosolve; amides such as formamide, dimethylformamide,dimethylacetamide or hexamethylphosphoric triamide; water; and mixturesthereof. Ethers and amides (particularly dioxane, tetrahydrofuran anddimethylformamide) are preferable.

[0470] The reaction temperature may depend on the starting materialcompounds, acids, solvents and/or other conditions to be used though thereaction may typically be performed at from −20° C. to the boilingpoint, and preferably from 0° C. to 100° C.

[0471] The reaction time may depend on the starting material compounds,acids, solvents, reaction temperature and/or other conditions to be usedthough the reaction may typically be performed for from 15 minutes to 48hours, and preferably from 30 minutes to 20 hours.

[0472] Step B3 is the substitution of a functional group by -YR₃ incompound (VIII). In this step, compound (VIII″), which corresponds tocompound (VIII) where the -YR₃ group comprises an alkoxyl, alkyltio oramino group, can be obtained by subjecting compound (VIII′), whichcorresponds to compound (VIII) where -YR₃ group comprises an —OH group,to any one of the following reactions (i)-(iv): (i) Mitsunobu reaction;(ii) etherification; (iii) alkane (or aryl) sulfonylation followed bythioetherification; or (iv) alkane (or aryl) sulfonylation followed byazido-complexing and then reductive reaction.

[0473] In step B3,

[0474] (i) Mitsunobu reaction for preparing compound (VIII′) may beperformed in an inert solvent in the presence of a phosphine (preferablytributylphosphine or triphenylphosphine) and an azodicarboxylatecompound (preferably diethyl azodicarboxylate or 1,1-dipiperidineazodicarboxylate);

[0475] (ii) etherification can be performed in the same manner as instep D1 described below;

[0476] (iii) alkane (or aryl) sulfonylation followed bythioetherification can be performed in the same manner as in step F1described below; and

[0477] (iv) alkane (or aryl) sulfonylation followed by azido-complexingand then reductive reaction can be performed in the same manner as instep G1 described below.

[0478] Further, the amino compound can be subjected to alkylation usingan alkyl halide substantially according to step H1 described later, orto any conventional reductive alkylation using an aldehyde or a ketone,to obtain an alkylamide.

[0479] Process C

[0480] wherein

[0481] R₂, R₃, W₁, W₂, X, Y′, B and R independently represent as definedabove.

[0482] In Process C, compound (IX) can be allowed to react in an inertsolvent in the presence of an acid to prepare compound (VII).

[0483] Any acid which can be used as an acid catalyst in conventionalreactions may be used in this process. Such acids include, but are notlimited to, for example: inorganic acids such as hydrochloric acid,hydrobromic acid, sulfuric acid, perchloric acid or phosphoric acid;Bronsted acids including organic acids such as acetic acid, formic acid,oxalic acid, methanesulfonic acid, p-toluenesulfonic acid,camphorsulfonic acid, trifluoroacetic acid or trifluoromethanesulfonicacid; Lewis acids such as zinc chloride, tin tetrachloride, borontrichloride, boron trifluoride or boron tribromide; and acidicion-exchange resins. Inorganic and organic acids (particularlyhydrochloric acid, acetic acid and trifluoroacetic acid) are preferable.

[0484] Any inert solvent can be used in this process as long as it isinert in the reaction. Such inert solvents include, but are not limitedto, for example: aliphatic hydrocarbons such as hexane, heptane, ligroinor petroleum ether, aromatic hydrocarbons such as benzene, toluene orxylene; halogenated hydrocarbons such as chloroform, dichloromethane,1,2-dichloroethane or carbon tetrachloride; esters such as methylacetate, ethyl acetate, propyl acetate, butyl acetate or diethylcarbonate; ethers such as diethyl ether, diisopropyl ether,tetrahydrofuran, dioxane, dimethoxyethane or di(ethylene glycol)dimethyl ether; alcohols such as methanol, ethanol, n-propanol,isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol,di(ethylene glycol), glycerine, octanol, cyclohexanol or methylcellosolve; amides such as formamide, dimethylformamide,dimethylacetamide or hexamethylphosphoric triamide; water; and mixturesthereof. Ethers and amides (particularly dioxane, tetrahydrofuran anddimethylformamide) are preferable.

[0485] The reaction may typically be performed at from −20° C. to theboiling point, and preferably from 0° C. to 80° C. though the reactiontemperature may depend on the starting material compounds, acids,solvents and/or other conditions to be used.

[0486] The reaction may typically be performed for from 15 minutes to 48hours, and preferably from 30 minutes to 20 hours though the reactiontime may depend on the starting material compounds, acids, solvents,reaction temperature and/or other conditions to be used.

[0487] Process D

[0488] wherein

[0489] R₂, R₃, W₁, W₂, X, Y′, B and R independently represent as definedabove, and Halo group represents any one of the halogen atoms describedabove.

[0490] In Process D, compound (X) can be allowed to react with a halidecompound having general formula of R₃-Halo in an inert solvent in thepresence of a base or silver oxide to prepare compound (IX).

[0491] Bases which may be used in this process include, for example:alkali metal carbonates such as lithium carbonate, sodium carbonate,potassium carbonate or cesium carbonate; alkali metal bicarbonates suchas lithium bicarbonate, sodium bicarbonate or potassium bicarbonate;alkali metal hydrides such as lithium hydride, sodium hydride orpotassium hydride; alkali metal hydroxides such as lithium hydroxide,sodium hydroxide or potassium hydroxide; alkali metal alkoxides such aslithium methoxide, sodium methoxide, sodium ethoxide or potassiumt-butoxide; and organic amines such as triethylamine, tributylamine,diisopropylethylamine, N-methylmorpholine, pyridine,4-(N,N-dimethylamino)pyridine, N,N-dimethylaniline, N,N-diethylaniline,1,5-diazabicyclo[4.3.0]nona-5-ene, 1,4-diazabicyclo[2.2.2]octane (DABCO)or 1,8-diazabicyclo[5.4.0]-7-undecene (DBU). Alkali metal hydrides(particularly, sodium hydride) are preferable.

[0492] Any inert solvent can be used in this process as long as it isinert in the reaction. Such inert solvents include, but are not limitedto, for example: aliphatic hydrocarbons such as hexane, heptane, ligroinor petroleum ether; aromatic hydrocarbons such as benzene, toluene orxylene; halogenated hydrocarbons such as chloroform, dichloromethane,1,2-dichloroethane or carbon tetrachloride; esters such as methylacetate, ethyl acetate, propyl acetate, butyl acetate or diethylcarbonate; ethers such as diethyl ether, diisopropyl ether,tetrahydrofuran, dioxane, dimethoxyethane or di(ethylene glycol)dimethyl ether; amides such as formamide, dimethylformamide,dimethylacetamide or hexamethylphosphoric triamide; and mixturesthereof. Ethers and amides (particularly dioxane, tetrahydrofuran anddimethylformamide) are preferable.

[0493] The reaction may typically be performed at from −20° C. to theboiling point, and preferably from 0° C. to 100° C. though the reactiontemperature may depend on the starting material compounds, acids,solvents and/or other conditions to be used.

[0494] The reaction may typically be performed for from 15 minutes to 48hours, and preferably from 30 minutes to 20 hours though the reactiontime may depend on the starting material compounds, bases, solvents,reaction temperature and/or other conditions to be used.

[0495] Process E

[0496] wherein

[0497] R₂, W₁, W₂, X, B, R and Halo group independently represent asdefined above.

[0498] In Process E, compound (XI) can be allowed to react with a halidehaving general formula (XII) in an inert solvent in the presence of abase or silver oxide to prepare compound (XIII).

[0499] Bases which may be used in the above-described reaction include,for example: alkali metal carbonates such as lithium carbonate, sodiumcarbonate, potassium carbonate or cesium carbonate; alkali metalbicarbonates such as lithium bicarbonate, sodium bicarbonate orpotassium bicarbonate; alkali metal hydrides such as lithium hydride,sodium hydride or potassium hydride; alkali metal hydroxides such aslithium hydroxide, sodium hydroxide or potassium hydroxide; alkali metalalkoxides such as lithium methoxide, sodium methoxide, sodium ethoxideor potassium t-butoxide; and organic amines such as triethylamine,tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine,4-(N,N-dimethylamino)pyridine, N,N-dimethylaniline, N,N-diethylaniline,1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane (DABCO)or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). Alkali metal hydrides andalkali metal carbonates (particularly, sodium hydride, potassiumcarbonate or cesium carbonate) are preferable.

[0500] Any inert solvent can be used in this process as long as it isinert in the reaction. Such inert solvents include, but are not limitedto, for example: aliphatic hydrocarbons such as hexane, heptane, ligroinor petroleum ether; aromatic hydrocarbons such as benzene, toluene orxylene; halogenated hydrocarbons such as chloroform, dichloromethane,1,2-dichloroethane or carbon tetrachloride; esters such as methylacetate, ethyl acetate, propyl acetate, butyl acetate or diethylcarbonate; ketones such as acetone or methyl ethyl ketone; ethers suchas diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane,dimethoxyethane or di(ethylene glycol) dimethyl ether; amides such asformamide, dimethylformamide, dimethylacetamide or hexamethylphosphorictriamide; and mixtures thereof. Ketones, ethers and amides(particularly, acetone, dioxane, tetrahydrofuran and dimethylformamide)are preferable.

[0501] The reaction may typically be performed at from −20° C. to theboiling point, and preferably from 0° C. to 100° C. though the reactiontemperature may depend on the starting material compounds, acids,solvents and/or other conditions to be used.

[0502] The reaction may typically be performed for from 15 minutes to 48hours, and preferably from 30 minutes to 20 hours though the reactiontime may depend on the starting material compounds, acids, solvents,reaction temperature and/or other conditions to be used.

[0503] Process F

[0504] wherein

[0505] R₂, R₃, W₁, W₂, X, B and R independently represent as definedabove.

[0506] Process F, which is a process for preparing compound (XIV), canbe performed by, in an inert solvent, allowing compound (XII) to reactwith methanesulfonyl chloride in the presence of a base followed byreaction with a mercaptan having general formula R₃SH in the presence ofa base.

[0507] Bases which may be used in step F1 include, for example: alkalimetal carbonates such as lithium carbonate, sodium carbonate orpotassium carbonate; alkali metal bicarbonates such as lithiumbicarbonate, sodium bicarbonate or potassium bicarbonate; alkali metalhydrides such as lithium hydride, sodium hydride or potassium hydride;alkali metal hydroxides such as lithium hydroxide, sodium hydroxide orpotassium hydroxide; alkali metal alkoxides such as lithium methoxide,sodium methoxide, sodium ethoxide or potassium t-butoxide; and organicamines such as triethylamine, tributylamine, diisopropylethylamine,N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine,N,N-dimethylaniline, N,N-diethylaniline,1,5-diazabicyclo[4.3.0]nona-5-ene, 1,4-diazabicyclo[2.2.2]octane (DABCO)or 1,8-diazabicyclo[5.4.0]-7-undecene (DBU). Organic amines(particularly, triethylamine) are preferable. Bases which can be used inthe first step can also be used in the second step of theabove-described reaction. Alkali metal hydrides (particularly, sodiumhydride) are preferable.

[0508] Any inert solvent can be used in the above-described reaction aslong as it is inert in the reaction. Such inert solvents include, butare not limited to, for example: aliphatic hydrocarbons such as hexane,heptane, ligroin or petroleum ether; aromatic hydrocarbons such asbenzene, toluene or xylene; halogenated hydrocarbons such as chloroform,dichloromethane, 1,2-dichloroethane or carbon tetrachloride; esters suchas methyl acetate, ethyl acetate, propyl acetate, butyl acetate ordiethyl carbonate; ethers such as diethyl ether, diisopropyl ether,tetrahydrofuran, dioxane, dimethoxyethane or di(ethylene glycol)dimethyl ether; amides such as formamide, dimethylformamide,dimethylacetamide or hexamethylphosphoric triamide; and mixturesthereof. Ethers and amides (particularly, dioxane, tetrahydrofuran anddimethylformamide) are preferable.

[0509] The reaction may typically be performed at from −20° C. to theboiling point, and preferably at from 0° C. to 100° C. though thereaction temperature may depend on the starting material compounds,acids, solvents and/or other conditions to be used.

[0510] The reaction may typically be performed for from 15 minutes to 48hours, and preferably from 30 minutes to 20 hours though the reactiontime may depend on the starting material compounds, acids, solvents,reaction temperature and/or other conditions to be used

[0511] wherein

[0512] R₂, R₃, W₁, W₂, X, Y, B and R independently represent as definedabove.

[0513] In Process G, compound (XIII) can be allowed to react withmethanesulfonyl chloride in the presence of a base in an inert solvent,and then with sodium azide to form azide compound which is then reducedto obtain compound (XV).

[0514] The same conditions as those used in step F1 may be used for thereaction with methanesulfonyl chloride and the following reaction withsodium azide as well except that base is not required in the secondstep. Further, the reductive reaction may be performed according toazide-to-amino conversion (i.e., the above described catalytic reductionand reaction with phosphine).

[0515] wherein

[0516] R₂, R₃, R₄, W₁, W₂, X, B and R independently represent as definedabove.

[0517] In Process I, compound (XV) is subjected to alkylation,aralkylation or arylation of the amino group to prepare compound (XVI).

[0518] Step H1 may be performed substantially according to any knownsynthesis process. For example, alkylation or aralkylation of the aminogroup may be performed by allowing the amino group to react with analkyl halide or aralkyl halide, while arylation may be performed byallowing the amino group to react with an aryl halide in the presence ofa base.

[0519] Bases which can be used in step H1 of Process H include, forexample: alkali metal carbonates such as lithium carbonate, sodiumcarbonate or potassium carbonate; alkali metal bicarbonates such aslithium bicarbonate, sodium bicarbonate or potassium bicarbonate; alkalimetal hydrides such as lithium hydride, sodium hydride or potassiumhydride; alkali metal hydroxides such as lithium hydroxide, sodiumhydroxide or potassium hydroxide; alkali metal alkoxides such as lithiummethoxide, sodium methoxide, sodium ethoxide or potassium t-butoxide;and organic amines such as triethylamine, tributylamine, diisopropylethylamine, N-methyl morpholine, pyridine,4-(N,N-dimethylamino)pyridine, N,N-dimethylaniline, N,N-diethylaniline,1,5 -diazabicyclo[4.3.0]nona-5-ene, 1,4-diazabicyclo[2.2.2]octane(DABCO) or 1,8-diazabicyclo[5.4.0]-7-undecene (DBU). Alkali metalbicarbonates are preferable.

[0520] wherein

[0521] R₂, R₃, R₄, W₁, W₂, X, B and R independently represent as definedabove.

[0522] Process I, which is a process for preparing compound (XVI), canbe performed by subjecting compound (XVII) to alkylation, aralkylationor arylation of the amino group as in Process H (step I1) and then tothe same reaction as step E1 (step I2). This step may be performed afterthe amino group is protected by any conventional protecting group.

[0523] wherein

[0524] R₂, W₂, X, B and R independently represent as defined above.

[0525] In Process J, a ketone or aldehyde having general formula (XIX)is converted to a cyanohydrin which is then subjected to hydrolysis oralcoholysis in the presence of acid to obtain compound (XX).

[0526] This process may be performed by using zinc iodide as a catalystin the presence or absence of an inert solvent.

[0527] Compound (XVII) may also be prepared by subjecting a ketone oraldehyde of general formula (XIX) to one of the conventional processesfor synthesizing amino acids, e.g. Strecker amino acid synthesis inwhich a ketone or aldehyde is reacted with hydrogen cyanide and ammonia.

[0528] wherein

[0529] R₁, Z, A and Boc group independently represent as defined above.

[0530] Process K, which is a process for preparing compound (VI), can beperformed by allowing compound (XXI) to react with a compound havinggeneral formula Z-H in an inert solvent in the presence of a base (stepK1) and then reducing the reaction product obtained (step K2).

[0531] Bases which may be used in step D1 described above can also beused in step K1 as well. Among all, alkali metal hydrides particularly,sodium hydride) are preferable. The same conditions as those for step D1described above may also be used in step K1.

[0532] Step K2, which is a process for the reduction of a nitro group inan aromatic compound, may be performed according to any conventionalprocess such as catalytic reduction, reduction using a combination of ametal and an acid (e.g., zinc-acetic acid, tin-alcohol ortin-hydrochloric acid) or reaction with sodium hydrosulfite.

[0533] Process L

[0534] wherein

[0535] R₁, A and Boc group independently represent as defined above.

[0536] Process L, which is a process for preparing compound (XXI), canbe performed by protecting the amino group in compound (XXIII) by usinga protecting group therefor, t-butoxycarbonyl group in an inert solventin the presence or absence of a base (step L1) and then subjecting theprotected compound to alkylation, arylation or aralkylation (step L2).

[0537] Step L1 is a process for introduction of a protecting group intothe amino group (Boc-lation) in which compound (XXIII) is allowed toreact with di-t-butyl dicarbonate in an inert solvent in the presence ofa base.

[0538] Step L2 is alkylation, arylation or aralkylation of theBoc-protected-amino group which can be performed according to anyconventionally known process.

[0539] Further, when an amino group is present in Z of theabove-described compounds (I)-(IV) and intermediate compound (VI),acylation, sulfonylation, or carbamoylation may be obtained byalkylation, arylation or aralkylation of the amino group or by any otherconventionally known process.

[0540] Process M

[0541] wherein

[0542] R₁, R₂, W₁, W₂, X, Z, A, B, R, Boc and Halo groups independentlyrepresent as defined above.

[0543] Process M is an alternative process for synthesizing compounds(I)-(III) in which -Y-R₃ group is a hydroxy group.

[0544] In Step M1, compound (XXV) is allowed to form an acetonidebetween the hydroxy group and carboxyl group in the molecule to preparecompound (XXVI). Step M1 may be performed by allowing compound (XXV) toreact with acetone or 2,2-dimethoxypropane in or without (preferablywithout) inert solvent in the presence of an acid.

[0545] Any acid may be used in the above-described reaction, which canbe used as an acid catalyst in conventional reactions. Such acidsinclude, but are not limited to, for example: inorganic acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid orphosphoric acid; Bronsted acids including organic acids such as aceticacid, formic acid, oxalic acid, methanesulfonic acid, p-toluenesulfonicacid, camphorsulfonic acid, trifluoroacetic acid ortrifluoromethanesulfonic acid; Lewis acids such as zinc chloride, tintetrachloride, boron trichloride, boron trifluoride or boron tribromide;and acidic ion-exchange resins. Inorganic and organic acids(particularly hydrochloric acid, acetic acid and trifluoroacetic acid)are preferable.

[0546] The reaction may typically be performed at from −20° C. to theboiling point, and preferably from 0° C. to 80° C. though the reactiontemperature may depend on the starting material compounds, acids and/orother conditions to be used.

[0547] The reaction may typically be performed for from 15 minutes to 48hours, and preferably from 30 minutes to 20 hours though the reactiontime may depend on the starting material compounds, acids, reactiontemperature and/or other conditions to be used.

[0548] In Step M2, compound (XXVI) may be allowed to react with compound(XII) in an inert solvent in the presence of a base substantiallyaccording to Process E to prepare compound (XXVII).

[0549] In Step M3, compound (XXVII) may be allowed to react in an inertsolvent in the presence of an acid substantially according to Process Cto prepare compound (XXVIII).

[0550] In Step M4, compound (XXVIII) may be allowed to react withcompound (VI) in an inert solvent in the presence of a condensationagent substantially according to Step B1 to prepare compound (XXIX).

[0551] In Step M5, compound (XXIX) may be allowed to react with water oran alcohol in an inert solvent (or the inert solvent may be the water oralcohol) in the presence of an acid substantially according to Step B2to prepare a compound having general formula (XXX) or (XXXI).

[0552] Compounds (I)-(IV) in which Y represents S(O)p group where prepresents an integer selected from 0-2 may be synthesized according tothe following process.

[0553] Process N

[0554] wherein

[0555] R₁, R₃, W₁, W₂, X, Z, A, B and R independently represent asdefined above.

[0556] Process N is a process for preparing compounds (XXXV), (XXXVI),(XXXVII), (XXXVIII), (XXXIX) and (XL).

[0557] In Step N1, compound (VI) is allowed to react with compound (XXI)substantially according to Step B1 described above to obtain compound(XXIII).

[0558] In Step N2, compound (XXXIII) is allowed to react substantiallyaccording to Step B2 described above to obtain compound (XXXIV).

[0559] In Step N3, compound (XXXIV) is allowed to react substantiallyaccording to Step A1 described above to obtain compound (XXXV). Step N3may be performed by allowing compound (XXXIV) to react with water in aninert solvent in the presence of a base.

[0560] Any inert solvent can be used in the above-described reaction aslong as it is inert in the reaction. Such inert solvents include, butare not limited to, for example: aliphatic hydrocarbons such as hexane,heptane, ligroin or petroleum ether; aromatic hydrocarbons such asbenzene, toluene or xylene; halogenated hydrocarbons such as chloroform,dichloromethane, 1,2-dichloroethane or carbon tetrachloride; ethers suchas diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane,dimethoxyethane or di(ethylene glycol) dimethyl ether; amides such asdimethylformamide, dimethylacetamide or hexamethylphosphoric triamide;alcohols such as methanol, ethanol or propanol; water; and mixturesthereof. Ethers, alcohols, amides, water and mixtures thereof arepreferable, alcohols and ethers are more preferable, and alcohols andtetrahydrofuran are most preferable.

[0561] Any bases which may not affect any other moieties than the targetmoiety in the compound can be used in the above-described reaction,including, for example: alkali metal carbonates such as lithiumcarbonate, sodium carbonate or potassium carbonate; alkali metalbicarbonates such as lithium bicarbonate, sodium bicarbonate orpotassium bicarbonate; alkali metal hydroxides such as lithiumhydroxide, sodium hydroxide or potassium hydroxide; metal alkoxides suchas lithium methoxide, sodium methoxide, sodium ethoxide or potassiumt-butoxide; and ammonia such as aqueous ammonia solution or concentratedammonia-methanol. Alkali metal hydroxides and metal alkoxides(particularly, alkali metal hydroxides and metal alkoxides) arepreferable.

[0562] The reaction may typically be performed at from −20° C. to 150°C., and preferably from 0° C. to 100° C. though the reaction temperaturemay depend on the starting material compounds, solvents and/or otherconditions to be used.

[0563] The reaction may typically be performed for from 30 minutes to 5days, and preferably from 2 to 72 hours though the reaction time maydepend on the starting material compounds, solvents, reactiontemperature and/or other conditions to be used.

[0564] Step N4, where compound (XXXV) is subjected to esterification toprepare compound (XXXVI), is performed substantially according to stepB1 described above except for using an alcohol having the generalformula ROH instead of compound (IV) and adapting any one of thefollowing processes(a)-(c): (a) acid halide process; (b) active esterprocess; or (c) mixed acid anhydration process.

[0565] Alternatively, Step N4 may also be performed by allowing compound(XXXV) to react with the alcohol of general formula ROH in an inertsolvent or in the alcohol in the presence of an acid. Any inert solventcan be used in the above-described reaction as long as it is inert inthe reaction. Such inert solvents include, but are not limited to, forexample: aliphatic hydrocarbons such as hexane, heptane, ligroin orpetroleum ether; aromatic hydrocarbons such as benzene, toluene orxylene; halogenated hydrocarbons such as chloroform, dichloromethane,1,2-dichloroethane or carbon tetrachloride; ethers such as diethylether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane ordi(ethylene glycol) dimethyl ether; amides such as dimethylformamide,dimethylacetamide or hexamethylphosphoric triamide; alcohols such asmethanol, ethanol or propanol; water; and mixtures thereof. Ethers,alcohols, amides and mixtures thereof are preferable, alcohols andethers are more preferable, and alcohol and tetrahydrofuran are mostpreferable.

[0566] Any acid may be used in the above-described reaction, which canbe used as acid catalyst in conventional reactions. Such acids include,but are not limited to, for example: inorganic acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid orphosphoric acid; Bronsted acids including organic acids such as aceticacid, formic acid, oxalic acid, methanesulfonic acid, p-toluenesulfonicacid, camphorsulfonic acid, trifluoroacetic acid ortrifluoromethanesulfonic acid; Lewis acids such as zinc chloride, tintetrachloride, boron trichloride, boron trifluoride or boron tribromide;and acidic ion-exchange resins. Inorganic and organic acids(particularly hydrochloric acid, acetic acid or trifluoroacetic acid)are preferable.

[0567] The reaction may typically be performed at from −20° C. to 150°C., and preferably from 0° C. to 60° C. though the reaction temperaturemay depend on the starting material compounds, solvents and/or otherconditions to be used.

[0568] The reaction may typically be performed for from 30 minutes to 5days, and preferably from 5 to 72 hours though the reaction time maydepend on the starting material compounds, solvents, reactiontemperature and/or other conditions to be used.

[0569] In step N5, compound (XXVI) may be allowed to react with acompound having general formula R₃-Halo (where R₃ is not hydrogen)substantially according to Step D1 described above to obtain compound(XXXVII).

[0570] In step N6, compound (XXXVII) may be subjected to esterhydrolysis substantially according to Step A1 described above to obtaincompound (XXXVI).

[0571] In step N7, compound (XXXVIII) may be allowed to react withammonia substantially according to Step B1 described above to obtaincompound (XXXIX).

[0572] In step N8, compound (XXXV) may be allowed to react with ammoniasubstantially according to Step B1 described above to obtain compound(XL).

[0573] In step N9, compound (XL) may be allowed to react with a compoundhaving general formula R₃-Halo (where R₃ is not hydrogen) substantiallyaccording to Step D1 described above to obtain compound (XXXIX).

[0574] Process O

[0575] wherein

[0576] R₁, R₃, W₁, W₂, X, Z, A, B and R independently represent asdefined above.

[0577] Process O is a method for preparing compounds (XLI), (XLII),(XLIII), (XLIV), (XLV) and (XLVI) by oxidization of a sulfide.

[0578] In Step O1, compound (XXXVII) is allowed to react with a peroxidesuch as m-chloroperoxybenzoic acid, hydrogen peroxide ort-butylhydroperoxide in an inert solvent in the presence or absence of abase to obtain compounds (XLI) and (XLII). Any inert solvent can be usedin the above-described reaction as long as it is inert in the reaction.Such inert solvents include, but are not limited to, for example:aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleumether; aromatic hydrocarbons such as benzene, toluene or xylene;halogenated hydrocarbons such as chloroform, dichloromethane,1,2-dichloroethane or carbon tetrachloride; ethers such as diethylether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane ordi(ethylene glycol) dimethyl ether; amides such as dimethylformamide,dimethylacetamide or hexamethylphosphoric triamide; alcohols such asmethanol, ethanol or propanol; water; and mixtures thereof. Halogenatedhydrocarbons, alcohols, amides, and mixtures thereof are preferable,alcohols and halogenated hydrocarbons are more preferable, and alcoholsand dichloromethane are most preferable.

[0579] Any bases which may not affect any other moieties than the targetmoiety in the compound can be used in the above-described reaction,including, for example: alkali metal carbonates such as lithiumcarbonate, sodium carbonate or potassium carbonate; alkali metalbicarbonates such as lithium bicarbonate, sodium bicarbonate orpotassium bicarbonate; alkali metal hydroxides such as lithiumhydroxide, sodium hydroxide or potassium hydroxide; metal alkoxides suchas lithium methoxide, sodium methoxide, sodium ethoxide or potassiumt-butoxide; and ammonia such as aqueous ammonia solution or concentratedammonia-methanol. Alkali metal carbonates and alkali metal bicarbonatesare preferable, and alkali metal bicarbonates are more preferable.

[0580] The reaction may typically be performed at from −20° C. to 150°C., and preferably from 0° C. to 60° C. though the reaction temperaturemay depend on the starting material compounds, solvents and/or otherconditions to be used.

[0581] The reaction may typically be performed for from 1 minute to 1day, and preferably from 5 minutes to 2 hours though the reaction timemay depend on the starting material compounds, solvents, reactiontemperature and/or other conditions to be used.

[0582] Step O2, which is a process for preparing compounds (XLIII) and(XLIV), can be performed by allowing compound (XXXVIII) to react with aperoxide such as m-chloroperoxybenzoic acid, hydrogen peroxide ort-butyl hydroperoxide in an inert solvent in the presence or absence ofa base substantially according to Step O1 above.

[0583] Step O3, which is a process for preparing compounds (XLV) and(XLVI), can be performed by allowing compound (XXXIX) to react with aperoxide such as m-chloroperoxybenzoic acid, hydrogen peroxide ort-butyl hydroperoxide in an inert solvent in the presence or absence ofa base substantially according to Step O1 above.

[0584] wherein

[0585] R₁, R₃, W₁, W₂, X, Z, A, B and R independently represent asdefined above, Z′ represents a benzyloxy group within the definition ofZ, Z″ represents a saturated heterocyclic oxy group (which may have 1-5substitution moieties α₁) within the definition of Z where thesubstitution moiety or moieties α₁ are protected, and Z′″ represents asaturated heterocyclic oxy group (which may have 1-5 substitutionmoieties α₁) within the definition of Z.

[0586] Process P is a process for preparing compounds having generalformula (I) according to the present invention where Z represents asaturated heterocyclic oxy group (which may have 1-5 substitutionmoieties α₁), i.e., compounds (LI), (LII), (LIII), (LIV), (LV) and(LVI).

[0587] In Step P1, compound (XXII′) where Z′ represents a benzyloxygroup is allowed to react in an inert solvent substantially according toStep K2 described above to obtain compound (XLVII).

[0588] In Step P2, compound (XLVII) is allowed to react with compound(XXXII) in an inert solvent substantially according to Step B1 describedabove to obtain compound (XLVIII).

[0589] In Step P3, compound (XLVIII) is allowed to react in an inertsolvent substantially according to Step B2 described above to obtaincompound (XLIX).

[0590] In Step P4, compound (XLIX) is allowed to react with a compoundhaving a Z group protected by substitution moiety or moieties α₁ (e.g.,methyl 1,2,3,4-tetra-O-acetyl-β-D-glucopyranuronate) in an inert solventsubstantially according to J. Am. Chem. Soc., 77, 3310 (1955) or Chem.Pharm. Bull. 39(8), 2124-2125 (1991) to obtain compound (L).

[0591] In Step P5, compound (L) is subjected to hydrolysis in an inertsolvent substantially according to J. Am. Chem. Soc., 77, 3310 (1955) orChem. Pharm. Bull. 39(8), 2124-2125 (1991) to obtain compound (LI).

[0592] In Step P6, compound (L) is subjected to hydrolysis in an inertsolvent substantially according to Step A1 described above to obtaincompound (LII).

[0593] In Step P7, compound (LI) is subjected to hydrolysis in an inertsolvent substantially according to Step A1 described above to obtaincompound (LII).

[0594] In Step P8, compound (LII) is allowed to react with ammonia in aninert solvent substantially according to Step B1 described above toobtain compound (LIII).

[0595] In Step P9, compound (LIII) is allowed to react with a compoundhaving general formula R₃-Halo (where R₃ is not hydrogen) in an inertsolvent substantially according to Step D1 described above to obtaincompound (LIV).

[0596] In Step P10, compound (LII) is subjected to esterificationsubstantially according to Step N4 described above to obtain compound(LV).

[0597] In Step P11, compound (LV) is allowed to react with a compoundhaving general formula R₃-Halo (where R₃ is not hydrogen) in an inertsolvent substantially according to Step D1 described above to obtaincompound (LVI).

[0598] wherein

[0599] R₁, R₃, W₁, W₂, X, Z′″, A, B and R independently represent asdefined above except that R₃ is not hydrogen.

[0600] In Process Q, sulfide compounds (LVII) and (LVIII) are prepared,and then compounds (LIX), (LX), (LXI), (LXII), (LXIII) and (LXIV) areprepared therefrom as well as from the sulfide compound (LVI) byoxidizing the sulfide compounds (LVI)-(LVIII) in the same manner asdescribed in Process O.

[0601] In Step Q1, compound (LVI) is subjected to hydrolysis in an inertsolvent substantially according to Step A1 described above to obtaincompound (LVII).

[0602] In Step Q2, compound (LVII) is allowed to react with ammonia inan inert solvent substantially according to Step B1 described above toobtain compound (LVIII).

[0603] Step Q3, which is a process for preparing compounds (LIX) and(LX), can be performed by allowing compound (LVI) to react with aperoxide such as m-chloroperoxybenzoic acid, hydrogen peroxide ort-butyl hydroperoxide in an inert solvent in the presence or absence ofa base substantially according to Step O1 above.

[0604] Step Q4, which is a process for preparing compounds (LXI) and(LXII), can be performed by allowing compound (LVII) to react with aperoxide such as m-chloroperoxybenzoic acid, hydrogen peroxide ort-butyl hydroperoxide in inert solvent in the presence or absence of abase substantially according to Step O1 above.

[0605] Step Q5, which is a process for preparing compounds (LXIII) and(LXIV), can be performed by allowing compound (LVIII) to react with aperoxide such as m-chloroperoxybenzoic acid, hydrogen peroxide ort-butyl hydroperoxide in an inert solvent in the presence or absence ofa base substantially according to Step O1 above.

[0606] Alternatively, compounds (I)-(IV) according to the presentinvention where Z represents a saturated heterocyclic oxy group (whichmay have 1-5 substitution moieties α₁) can also be synthesized accordingto the following process.

[0607] wherein

[0608] R₁, R₂, R₃, W₁, W₂, X, Y′, Z″, Z′″, A, B and R independentlyrepresent as defined above.

[0609] Process R is a process for preparing compounds having generalformula (I) or (IV) according to the present invention where Zrepresents a saturated heterocyclic oxy group (which may have 1-5substitution moieties α₁) which may be protected, i.e., compounds(LXVII), (LXVIII), (LXIX) or (LXXII).

[0610] In Step R1, compound (XLVII) is allowed to react with compound(VII) in an inert solvent substantially according to Step B1 describedabove to obtain compound (LXV).

[0611] In Step R2, compound (LXV) is allowed to react in an inertsolvent substantially according to Step B2 described above to obtaincompound (LXVI).

[0612] In Step R3, compound (LXVI) is allowed to react with a compoundhaving a Z group protected by substitution moiety or moieties α₁ (e.g.,methyl 1,2,3,4-tetra-O-acetyl-β-D-glucopyranuronate) in an inert solventsubstantially according to J. Am. Chem. Soc., 77, 3310 (1955) or Chem.Pharm. Bull. 39 (8), 2124-2125 (1991) to obtain compound (LXVII).

[0613] In Step R4, compound (LXVII) is subjected to hydrolysis in aninert solvent substantially according to J. Am. Chem. Soc., 77, 3310(1955) or Chem. Pharm. Bull. 39 (8), 2124-2125 (1991) to obtain compound(LXVIII).

[0614] In Step R5, compound (LXVIII) is allowed to react with ammonia inan inert solvent substantially according to Step B1 described above toobtain compound (LXIX).

[0615] In Step R6, compound (LXVI) is subjected to hydrolysis in aninert solvent substantially according to Step A1 described above toobtain compound (LXX).

[0616] In Step R7, compound (LXX) is allowed to react with ammonia in aninert solvent substantially according to Step B1 described above toobtain compound (LXXI).

[0617] In Step R8, compound (LXXI) is allowed to react with a compoundhaving a Z group protected by substitution moiety or moieties α₁ (e.g.,methyl 1,2,3,4-tetra-O-acetyl-β-D-glucopyranuronate) in an inert solventsubstantially according to J. Am. Chem. Soc., 77, 3310 (1955) or Chem.Pharm. Bull. 39 (8), 2124-2125 (1991) to obtain compound (LXXII).

[0618] In Step R9, compound (LXXII) is subjected to hydrolysis in aninert solvent substantially according to J. Am. Chem. Soc., 77, 3310(1955) or Chem. Pharm. Bull. 39 (8), 2124-2125 (1991) to obtain compound(LXIX).

[0619] Compounds (I)-(IV) where Z represents a hydroxy group can besynthesized according to the following process.

[0620] Process S

[0621] Process S is a process for preparing compounds (XXXV)-(XL)obtained in Process N and compounds (XXXVI)-(XLVI) obtained in Process Owhere Z represents a hydroxy group.

[0622] Compounds (VI) and (XXVII), which are starting materials inProcesses N and O, where Z represents a hydroxy group can be subjectedto reactions according to Processes N and O to obtain compounds(XXXV)-(XL) and (XLI)-(XLVI) where Z represents a hydroxy group.

[0623] Compound (VI) where Z represents a hydroxy group (i.e., compound(XLVI)) can be prepared according to step P1 described above.

[0624] Alternatively, starting material compounds having a substitutionmoiety or moieties protected may be used instead of those shown in theabove-described chemical synthesis pathways and after reactions theprotecting group or groups can be removed to obtain the target compoundsshown in the pathways.

[0625] For example, when substitution moiety γ represents a hydroxygroup, compounds which have protected hydroxy group(s) can be subjectedto the above-described chemical reactions and then the protectinggroup(s) can be removed to obtain the target compounds shown in theabove-described chemical synthesis pathways.

[0626] After completion of the reactions, the target compounds obtainedin the respective steps may be collected from the reaction mixturesaccording to any conventional method. For example, the target compoundcan be collected by: appropriately neutralizing the reaction products;removing, if any, insoluble materials by filtration; then adding organicsolvents which are not miscible with water (e.g. ethylacetate);-separating the organic phase containing the target compoundwhich is then washed with, for example, water, and dried on anhydrousmagnesium sulfate, anhydrous sodium sulfate, anhydrous sodiumbicarbonate or the like; and removing solvent by distillation. Thetarget compounds can be separated and purified by a suitable combinationof any conventional methods for separation/purification of organiccompounds such as recrystallization and reprecipitation, chromatographyusing appropriate eluant(s).

[0627] Further, the compounds according to the present invention can beobtained according, for example, to the conventional method describedbelow.

[0628] Physiologically active compounds (e.g. compounds disclosed inJapanese Patent Application Laid-Open H9 (1997)-295970) may beadministered to homeotherm and biological samples may be collected fromthe animal after a predetermined time. Next, target compound(s) in thebiological sample may be isolated and purified by any separation methodsuch as column chromatography to obtain the compound(s) according to thepresent invention.

[0629] The term “homeotherm” refers to an animal which is capable ofthermoregulation to maintain its constant body temperature regardless ofatmospheric temperature, including: warm blooded animals, e.g. mammalssuch as a human, dog, monkey, rabbit, guinea pig, rat or mouse; andbirds such as a chicken.

[0630] The term “biological sample” includes, for example, plasma,urine, feces (bile), liver and kidney.

[0631] The above-described compounds (I)-(IV) according to the presentinvention and pharmacologically acceptable salts, esters or amidesthereof have the following activities: PPARγ activation activity;insulin resistance improving activity; hypoglycemic activity;anti-inflammatory activity; immunoregulatory activity; aldose reductaseinhibiting activity; 5-lipoxygenase inhibiting activity; inhibition oflipid peroxide expression; PPAR activation activity; anti-osteoporoticactivity; leukotriene antagonistic activity; enhancement of adipose cellformation; inhibition of carcinoma cell proliferation; and calciumantagonistic activity. The present invention provides treatment and/orprevention of, for example: diabetes mellitus; hyperlipidemia; obesity;impaired glucose tolerance; hypertension; fatty liver; diabeticcomplications such as retinopathy, nephrosis, neuropathy, cataract orcoronary artery disease; arteriosclerosis; gestational diabetesmellitus; polycystic ovary syndrome; cardiovascular diseases such asischemic heart disease; cell injury lesions including those caused bynon-atherosclerosis or ischemic heat disease such as cerebral injurycaused by stroke; gout; inflammatory diseases such as arthrosteitis,pain, fervesence, rheumatic arthritis, inflammatory enteritis, acne,sunburn, psoriasis, eczema, allergic disease, asthma, GI ulcer,cachexia, autoimmune disease and pancreatitis; cancer; osteoporosis; andcataract by administering to an animal (including a human) in needthereof, an effective amount of a compound of the formula (I)-(IV).

[0632] Further, pharmaceutical compositions which comprise at least onecompound selected from the group consisting of the above-describedcompounds (I)-(IV) according to the present invention andpharmacologically acceptable salts, esters or amides thereof and atleast one compound selected from the group consisting of RXR activators(RXR agonists), α-glucosidase inhibitors, aldose reductase inhibitors,biguanides, statine type compounds, squalene synthesis inhibitors,fibrate type compounds, LDL disassimilation promotors andangiotensin-converting enzyme-inhibitors (particularly preferable arecompositions for prevention and/or treatment of diabetes or diabeticcomplication) are also useful.

[0633] The above-described compounds (I)-(IV) according to the presentinvention or pharmacologically acceptable salts, esters or amidesthereof can be used for treatment or prevention of the above-describeddiseases by administering the compound alone or in combination with asuitable pharmacologically acceptable carrier in a suitable dosage form,such as tablets, capsules, granules, powders or syrups for oraladministration, or injections or suppositories for parenteraladministration. Other usual dosage forms, e.g., ointments and sprays,may be used for alternate administration routes.

[0634] Such formulations may be prepared according to any well knowntechnique, and may also include carrier(s) such as excipients,lubricants, binders, disintegrators, stabilizers, corrigents and/ordiluents. Excipients include both organic and inorganic excipients.Examples of organic excipients are, for example: glucose derivativessuch as lactose, sucrose, glucose, mannitol and sorbitol; starchderivatives such as corn starch, potato starch, ax starch and dextrin;cellulose derivatives such as crystalline cellulose; gum Arabic;dextran; and Pullulan. Examples of inorganic excipients are, forexample: silicate derivatives such as light anhydrous silicic acid,synthetic aluminium silicate, calcium silicate and magnesiummetaaluminosilicate; phosphates such as calcium hydrogen phosphate;carbonates such as calcium carbonate; and sulfates such as calciumsulfate. Lubricants include, for example: stearic acid and metalstearates such as calcium stearate and magnesium stearate; talc;colloidal silica; waxes such as bee gum or spermaceti; boric acid;adipic acid; sulfates such as sodium sulfate; glycol; fumaric acid;sodium benzoate; DL leucine; sodium fatty acid salt; lauryl sulfatessuch as lauryl sodium sulfate or lauryl magnesium sulfate; silicatessuch as silicic anhydride or silicic hydrate; and the above-describedstarch derivatives. Binders include, for example, hydroxypropylcellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, Macrogoland the above-described excipient compounds. Disintegrators include, forexample: cellulose derivatives such as low substitutedhydroxypropylcellulose, carboxymethyl cellulose, calcium carboxymethylcellulose, internal-crosslinked sodium carboxymethyl cellulose;chemically modified starch-cellulose compounds such as carboxymethylstarch, sodium carboxymethyl starch or cross-linkedpolyvinylpyrrolidone. Stabilizers include, for example: p-hydroxybenzoicesters such as methylparaben or propylparaben; alcohols such aschlorobutanol, benzyl alcohol or phenylethyl alcohol; benzalkoniumchloride; phenols such as phenol or cresol; thimerosal; dehydroaceticacid; and sorbic acid. Corrigents include sweeteners, souring agents andflavors which are commonly used in the art.

[0635] The dose will vary depending on the disease state, age of thepatient, e.g. human, the chosen route of administration, etc. In thecase of oral administration, a desirable single unit dose contains thecompound of the present invention in an amount of 0.001 to 500 mg/kg ofbody weight and preferably from 0.01 to 50 mg/kg of body weight. In thecase of intravenous administration, a desirable single unit dosecontains the compound of the present invention in an amount of 0.005 to50 mg/kg of body weight and preferably 0.05 to 5 mg/kg of body weight.It is desirable to administer the single unit dose one time or severaltimes throughout the day depending on the conditions of the patient.Other dosage forms for other administration routes will also be withinthe aforesaid ranges and preferably in an amount of 0.01 to 50 mg/kg ofbody weight. Dosage for treatment or prevention of a specific patient inneed thereof is determined by those skilled in the art by applying usualtechniques.

[0636] The following examples, preparation examples and test examplesare intended to further illustrate the present invention and are notintended to limit the scope of this invention.

EXAMPLE 1

[0637] Methyl3-[4-[6-(4-adamantan-1-ylphenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]phenyl]-2-(4-fluorobenzyloxy)propionate(Methyl Ester of Exemplification Compound Number 1-1)

[0638] A mixture of methyl3-[4-[4-(4-adamantan-1-yl)phenoxy)-2-(N-t-butoxycarbonyl-N-methylamino)phenylaminocarbonylmethoxy]phenyl-2-(4-fluorobenzyloxy)propionate(0.8 g) and 4N hydrogen chloride/dioxane (20 ml) was stirred at roomtemperature for 1 hour. The solvent of the reaction mixture wasevaporated under reduced pressure. The residue was neutralized withsodium hydrogencarbonate and extracted with ethyl acetate. The extractwas washed with saturated aqueous sodium chloride solution and driedover anhydrous sodium sulfate. The ethyl acetate was evaporated underreduced pressure. The residue crystallized in hexane: ethyl acetate=4:1solution and the crystals were isolated by filtration to afford thetitle compound (0.43 g, mp 118-120° C.).

EXAMPLE 2

[0639]3-[4-[6-(4-Adamantan-1-ylphenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]phenyl]-2-(4-fluorobenzyloxy)propionicAcid (Exemplification Compound Number 1-1)

[0640] A mixture of methyl3-[4-[6-(4-adamantan-1-ylphenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]phenyl]-2-(4-fluorobenzyloxy)propionate(0.25 g), aqueous 2N sodium hydroxide solution (2 ml) and methanol (5ml) was stirred at room temperature for 2 hours. To the reaction mixturewas added tetrahydrofuran (5 ml) and the mixture was stirred for 4hours. The reaction mixture was poured into water and neutralized withhydrochloric acid and sodium hydrogencarbonate and extracted with ethylacetate. The extract was washed with saturated aqueous sodium chloridesolution and dried over anhydrous sodium sulfate. The ethyl acetate wasevaporated under reduced pressure. The residue crystallized in ethylacetate and the crystals were isolated by filtration to afford the titlecompound (0.23 g, mp 148-149° C.).

EXAMPLE 3

[0641] Methyl3-[4-[6-(3,5-di-t-butyl-4-hydroxyphenylthio)-1-methyl-1H-benzimidazol-2-ylmethoxy]phenyl]-2-(4-fluorobenzyloxy)propionate(Methyl Ester of Exemplification Compound Number 1-86)

[0642] A mixture of methyl3-[4-[4-(3,5-di-t-butyl-4-hydroxyphenylthio)-2-(N-t-butoxycarbonyl-N-methylamino)phenylaminocarbonylmethoxy]phenyl-2-(4-fluorobenzyloxy)propionate(0.5 g) and 4N hydrogen chloride/dioxane was treated in a similarprocedure to that described in Example 1 to afford the title compound(0.24 g, Rf=0.15 (thin layer chromatography on silica gel using hexane:ethyl acetate=3:1 as the eluant)).

EXAMPLE 4

[0643]3-[4-[6-(3,5-Di-t-butyl-4-hydroxyphenylthio)-1-methyl-1H-benzimidazol-2-ylmethoxy]phenyl]-2-(4-fluorobenzyloxy)propionicAcid (Exemplification Compound Number 1-86)

[0644] Reaction and isolation were conducted in a similar procedure tothat described in Example 2 using methyl3-[4-[6-(3,5-di-t-butyl4-hydroxyphenylthio)-1-methyl-1H-benzimidazol-2-ylmethoxy]phenyl]-2-(4-fluorobenzyloxy)propionate(0.22 g), aqueous 2N sodium hydroxide solution (2 ml) and methanol (5ml) to afford the title compound (0.13 g, mp 40-46° C.).

EXAMPLE 5

[0645] Methyl4-(1-methyl-6-methoxy-1H-benzimidazol-2-ylmethoxy)phenyllactate (MethylEster of Exemplification Compound Number 1-177)

[0646] A mixture of4-(5,5-dimethyl-2-oxodioxolan-3-ylmethyl)phenoxyaceto-N-[2-(N-t-butoxycarbonyl-N-methylamino)4-methoxyphenyl]amide(4.5 g), methanol (40 ml) and 4N hydrogen chloride/dioxane (40 ml) wastreated in a similar procedure to that described in Example 1 and theresidue was recrystallized from dimethylformamide/ethyl acetate toafford the title compound (1.84 g, mp 169-170° C.).

EXAMPLE 6

[0647] 4-(1-Methyl-6-methoxy-1H-benzimidazol-2-ylmethoxy)phenyllacticAcid Hydrochloride (Hydrochloride of Exemplification Compound Number1-177)

[0648] A mixture of methyl4-(1-methyl-6-methoxy-1H-benzimidazol-2-ylmethoxy)phenyllactate (0.2 g),methanol (5 ml) and 4N hydrogen chloride/dioxane (10 ml) was stirred atroom temperature for 2 hours. The reaction mixture was concentrated togive crystals. The crystals were washed with a mixture of methanol andether to afford the title compound (0.2 g, mp 193-195° C.).

EXAMPLE 7

[0649] 4-(1-Methyl-6-methoxy-1H-benzimidazole-2-ylmethoxy)phenyllacticAcid (Exemplification Compound Number 1-177)

[0650] A mixture of methyl4-(1-methyl-6-methoxy-1H-benzimidazol-2-ylmethoxy)phenyllactate (0.15g), concentrated hydrochloric acid (2 ml) and dioxane (2 ml) was heatedat reflux for 3 hours. The reaction mixture was concentrated and thewater of the residue was removed by azeotropic distillation in dioxaneand the crystals were isolated by filtration to afford the titlecompound (0.15 g, mp 216-218° C.).

EXAMPLE 8

[0651] Methyl2-ethoxy-3-[4-(1-methyl-6-methoxy-1H-benzimidazol-2-ylmethoxy)phenyl]propionate(Methyl Ester of Exemplification Compound Number 1-179)

[0652] A mixture of methyl4-(1-methyl-6-methoxy-1H-benzimidazol-2-ylmethoxy)phenyl]propionate (0.6g), methyl iodide (0.52 ml), silver oxide (0.88 g) and dimethylformamide(15 ml) was heated for 4.5 hours and then stirred at room temperatureovernight. The insoluble material in the reaction mixture was removed byfiltration and the filtrate was concentrated. The residue waspartitioned between ethyl acetate and water and the extract was washedwith saturated aqueous sodium chloride solution and dried over anhydroussodium sulfate. The ethyl acetate was evaporated under reduced pressure.The residue was chromatographed on a silica gel column usinghexane:ethyl acetate=2:3 as the eluant to afford the title compound(0.15 g, mp 88-92° C.).

EXAMPLE 9

[0653]2-Ethoxy-3-[4-(1-methyl-6-methoxy-1H-benzimidazol-2-ylmethoxy)phenyl]propionicAcid Hydrochloride (Hydrochloride of Exemplification Compound Number1-179)

[0654] A mixture of methyl2-ethoxy-3-[4-(1-methyl-6-methoxy-1H-benzimidazol-2-ylmethoxy)phenyl]propionate(0.17 g), concentrated hydrochloric acid (2 ml) and dioxane (2 ml) washeated at reflux for 1.5 hours. The reaction mixture was concentratedand the water of the residue was removed by azeotropic distillation indioxane and the crystals were isolated by filtration to afford the titlecompound (0.16 g, mp 143-146° C.).

EXAMPLE 10

[0655] Methyl4-[6-(4hydroxy-2,3,5-trimethylphenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]phenyllactate(Methyl Ester of Exemplification Compound Number 1-170)

[0656] The reaction was conducted in a similar procedure in that ofExample 1 using4-(5,5-dimethyl-2-oxodioxolan-3-ylmethyl)phenoxyaceto-N-[2-(N-t-butoxycarbonyl-N-methylamino)-4-(4-methoxymethoxy-2,3,5-trimethylphenoxy)phenyl]amide(5.98 g), methanol (50 ml) and 4N hydrogen chloride/dioxane (50 ml). Thesolvent of the reaction mixture was evaporated under reduced pressureand the residue was neutralized with sodium hydrogencarbonate andextracted with ethyl acetate. The extract was washed with saturatedaqueous sodium chloride solution and dried over anhydrous sodiumsulfate. The ethyl acetate was evaporated under reduced pressure. Theresidue was chromatographed on a silica gel column using hexane: ethylacetate=1:2-1:3 as the eluant to afford the title compound (3.15 g, mp172-173° C.).

EXAMPLE 11

[0657] Methyl4-[6-(4-hydroxy-2,3,5-trimethylphenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]phenyllactateHydrochloride (Methyl Ester Hydrochloride of Exemplification CompoundNumber 1-170)

[0658] The title compound (0.195 g, mp 113-119° C.) was obtained by asimilar procedure to that described in Example 6 using methyl4-[6-(4-hydroxy-2,3,5-trimethylphenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]phenyllactate(0.2 g), methanol (2 ml) and 4N hydrogen chloride/dioxane (5 ml).

EXAMPLE 12

[0659] Methyl4-[6-(3,5-di-t-butyl-4-hydroxyphenylthio)-1-methyl-1H-benzimidazol-2-ylmethoxy]phenyllactate(Methyl Ester of Exemplification Compound Number 1-87)

[0660] The title compound (2.6 g, mp 155-156° C.) was obtained by asimilar procedure to that described in Example 1 using4-(5,5-dimethyl-2-oxodioxolan-3-ylmethyl)phenoxyaceto-N-[2-(N-t-butoxycarbonyl-N-methylamino)-4-(3,5-di-t-butyl-4-hydroxyphenylthio)phenyl]amide(5.1 g), methanol (40 ml) and 4N hydrogen chloride/dioxane (40 ml).

EXAMPLE 13

[0661] Methyl4-[6-(3,5-di-t-butyl-4-hydroxyphenylthio)-1-methyl-1H-benzimidazol-2-ylmethoxy]phenyllactateHydrochloride (Methyl Ester Hydrochoride of Exemplification CompoundNumber 1-87)

[0662] The title compound (0.19 g, mp 135-139° C.) was obtained by asimilar reaction and purification to those in Example 6 using methyl4-[6-(3,5-di-t-butyl-4-hydroxyphenylthio)-1-methyl-1H-benzimidazol-2-ylmethoxy]phenyllactate(0.2 g) and 4N hydrogen chloride/dioxane (10 ml)

EXAMPLE 14

[0663] 4(6-Methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenylalaninemethyl ester (Methyl Ester of Exemplification Compound Number 3-177)

[0664] A mixture of methyl2-azido-3[4-(6-methoxy-1-methyl-1H-benzimidazol-2-yl)phenyl]propionate(2.42 g) in tetrahydrofuran (20 ml) and triphenylphosphine (1.6 g) wasstirred at room temperature for 1.5 hours. To the reaction mixture wasadded water (5 ml) and the mixture was stirred at 60° C. for 1 hour. Thereaction mixture was partitioned between ethyl acetate and water. Theextract was washed with saturated aqueous sodium chloride solution anddried over anhydrous magnesium sulfate. The ethyl acetate was evaporatedunder reduced pressure. The residue was chromatographed on a silica gelcolumn using ethyl acetate-tetrahydrofuran as the eluant to afford thetitle compound (1.63 g, mp 108-111° C.).

EXAMPLE 15

[0665]N-(2-Benzoylphenyl)-4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenylalanineMethyl Ester (Methyl Ester of Exemplification Compound Number 3-188)

[0666] A mixture of4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenylalanine methylester (1.1 g), 2-benzoylcyclohexanone (0.7 g), palladium on carbon (10%,0.2 g) and anisole (15 ml) was heated at reflux for 21 hours. Insolublematerial of the reaction mixture was removed by filtration and theanisole of the filtrate was evaporated under reduced pressure. Theresidue was chromatographed on a silica gel column using hexane:ethylacetate=1:2 as the eluant to afford the title compound (0.95 g, Rf=0.51(thin layer chromatography on silica gel using hexane:ethyl acetate=1:3as the eluant)).

EXAMPLE 16

[0667]N-(2-Benzoylphenyl)-4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenylalanineMethyl Ester Hydrochloride (Methyl Ester Hydrochloride ofExemplification Compound Number 3-188)

[0668] The title compound (0.195 g, mp 132-136° C.) was obtained by asimilar procedure to that described in Example 6 usingN-(2-benzoylphenyl)-4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenylalaninemethyl ester (0.45 g), methanol (2 ml) and 4N hydrogen chloride/dioxane(10 ml).

EXAMPLE 17

[0669]N-(2-Benzoylphenyl)-4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenylalanine(Exemplification Compound Number 3-188)

[0670] The title compound (0.44 g, mp 140-146° C.) was obtained by asimilar procedure to that described in Example 6 usingN-(2-benzoylphenyl)-4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenylalaninemethyl ester (0.45 g), concentrated hydrochloric acid (5 ml) and dioxane(5 ml).

EXAMPLE 18

[0671] 4-(6-Methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenylalanineDihydrochloride (Dihydrochloride of Exemplification Compound Number3-177)

[0672] The title compound (0.11 g, mp 235-237° C. (dec)) was obtained bya similar procedure to that described in Example 6 using4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenylalanine methylester (0.12 g), concentrated hydrocloric acid (2 ml) and dioxane (2 ml).

EXAMPLE 19

[0673]4-[6-(4-Amino-3,5-dimethylphenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]-N-(2-benzoylphenyl)phenylalanineMethyl Ester (Methyl Ester of Exemplification Compound Number 3-285)

[0674] The title compound (0.62 g, Rf=0.39: thin layer chromatography onsilica gel (LiChroprep NH2 (Merck)) using hexane:ethyl acetate=1:2 asthe eluant) was obtained by a similar procedure to that described inExample 6 using4-[2-(N-t-butoxycarbonyl-N-methylamino)-4-(4-t-butoxycarbonylamino-3,5-dimethylphenoxy)phenylaminocarbonylmethoxy]-N-(2-benzoylphenyl)phenylalaninemethyl ester (1.05 g), methanol (5 ml) and 4N hydrogen chloride/dioxane(10 ml) and then by liquid chromatography (LiChroprep NH2 (Merck)) usinghexane:ethyl acetate=1:2 as the eluant.

EXAMPLE 20

[0675] 4-[6-(4Amino-3,5dimethylphenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]-N-(2-benzoylphenyl)phenylalanineDihydrochloride (Dihydrochloride of Exemplification Compound Number3-285)

[0676] A mixture of4-[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]-N-(2-benzoylphenyl)phenylalaninemethyl ester (0.25 g), lithium hydroxide monohydrate (0.04 g),tetrahydrofuran (5 ml) and water (2 ml) was stirred at room temperaturefor 3 hours. The reaction mixture was neutralized with 1N hydrochloricacid and partitioned between ethyl acetate and water. The extract waswashed with saturated aqueous sodium chloride solution and dried overanhydrous sodium sulfate and then concentrated under reduced pressure.The residue was chromatographed on LiChroprepDIOL (Merck) using ethylacetate as the eluant to give a yellow material. To a solution of thematerial in tetrahydrofuran (3 ml) was added 4N hydrogenchloride/dioxane (1 ml) to give crystals. The crystals were isolated byfiltration to afford the title compound (0.11 g, mp 148-155° C.).

EXAMPLE 21

[0677]4-[6-[4-(4-Trifluoromethylphenylureido)-3,5-dimethylphenoxy]-1-methyl-1H-benzimidazol-2-ylmethoxy]-N-(2-benzoylphenyl)phenylalanineMethyl Ester (Methyl Ester of Exemplification Compound Number 3-299)

[0678] To a solution of4-[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]-N-(2-benzoylphenyl)phenylalaninemethyl ester (0.35 g) in tetrahydrofuran (5 ml) was added4-trifluorophenylisocyanate (0.1 ml). The mixture was stirred at roomtemperature for 20 hours and then was concentrated under reducedpressure. The residue was chromatographed on LiChroprepDIOL (Merck)using hexane:ethyl acetate=1:3 as the eluant to afford the titlecompound (0.43 g, Rf=0.59: thin layer chromatography on silica gel(LiChroprepDIOL (Merck)) using ethyl acetate as the eluant).

EXAMPLE 22

[0679]4-[6-[4-(4-Trifluoromethylphenylureido)-3,5-dimethylphenoxy]-1-methyl-1H-benzimidazol-2-ylmethoxy]-N-(2-benzoylphenyl)phenylalanine(Exemplification Compound Number 3-299)

[0680] A mixture of4-[6-[4-4-trifluoromethylphenylureido)-3,5-dimethylphenoxy]-1-methyl-1H-benzimidazol-2-ylmethoxy]-N-(2-benzoylphenyl)phenylalaninemethyl ester (0.4 g), lithium hydroxide monohydrate (0.042 g),tetrahydrofuran (5 ml) and water (2 ml) was sired at room temperaturefor 4 hours and then allowed to stand for 2 days. The reaction mixturewas neutralized with 1N hydrochloric acid and partitioned between ethylacetate and water. The extract was washed with saturated aqueous sodiumchloride solution and dried over anhydrous sodium sulfate and thenconcentrated under reduced pressure. To a solution of the residualyellow material in tetrahydrofuran (10 ml) was added 4N hydrogenchloride/dioxane (4 ml) and then the solvent was evaporated underreduced pressure. To the residue was added ether to give crystals. Thecrystals were isolated by filtration to afford the title compound (0.38g, mp 165-172° C.).

EXAMPLE 23

[0681]N-Methanesulfonyl-4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenylalanineMethyl Ester (Methyl Ester of Exemplification Compound Number 3-261)

[0682] To a solutionof4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenylalanine methylester (0.2 g) in tetrahydrofuran (6 ml) and dimethylformamide (3 ml)were added successively pyridine (0.09 ml) and methanesulfonic anhydride(0.14 g). The mixture was stirred at room temperature for 3 hours andwas partitioned between ethyl acetate and water. The extract was washedwith saturated aqueous sodium chloride solution, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure to givecrystals. The crystals were isolated by filtration to afford the titlecompound (0.12 g, mp 168-171° C.).

EXAMPLE 24

[0683]N-Methanesulfonyl-4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenylalanineHydrochloride (Hydrochloride of Exemplification Compound Number 3-261)

[0684] The title compound (0.11 g, mp 211-217 (dec)) was obtained by asimilar procedure to that described in Example 6 usingN-methanesulfonyl-4(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenylalaninemethyl ester (0.11 g), concentrated hydrochloric acid (1 ml) and dioxane(4 ml).

EXAMPLE 25

[0685] Ethyl3-[4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]-2-mercaptopropionate(Eethyl Ester of Exemplification Compound Number 5-1)

[0686] A solution of potassium hydroxide (30 g) in water (150 ml) wasadded to a suspension of5-[4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)benzyl]thiazolidin-2,4-donehydrochloride (8.0 g) in ethanol (150 ml). The mixture was stirred at75° C. for 4 hours and poured into ice-water and acidified withhydrochloric acid and stirred for 30 minutes to give crystals. Thecrystals were isolated by filtration and washed with water and driedunder reduced pressure.

[0687] A solution of the crystals in anhydrous ethanol (100 ml) and 4Nhydrogen chloride/dioxane (200 ml) was allowed to stand at roomtemperature for 2 days. The solvent was evaporated under reducedpressure. To the residue was added water and the mixture was neutralizedwith aqueous sodium hydrogencarbonate solution and then partitionedbetween ethyl acetate and water. The extract was washed with saturatedaqueous sodium chloride solution and dried over anhydrous sodium sulfateand then concentrated under reduced pressure. The residue waschromatographed on a LiChroprepNH2 (Merck) column using hexane:ethylacetate=4:1 as the eluant to afford the title compound (3.93 g, Rf=0.45:thin layer chromatography on silica gel (LiChroprepNH2 (Merck)) usinghexane:ethyl acetate=1:5 as the eluant).

EXAMPLE 26

[0688] Ethyl3-[4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylthiopropionate(Ethyl Ester of Exemplification Compound Number 5-4)

[0689] To a solution of ethyl3-[4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]-2-mercaptopropionate(3.9 g) in tetrahydrofuran (80 ml) were added successively methyl iodide(0.87 ml) and triethylamine (1.94 ml). The mixture was allowed to standovernight. To the mixture was further added methyl iodide (0.6 ml) andtriethylamine (1.3 ml) and then the mixture was stirred for 70 minutes.The solvent of the reaction mixture was evaporated under reducedpressure. The residue was partitioned between ethyl acetate and water.The extract was washed with saturated aqueous sodium chloride solutionand dried over anhydrous magnesium sulfate and then concentrated underreduced pressure. The residue was chromatographed on a silica gel columnusing hexane:ethyl acetate=1:1 as the eluant to afford the titlecompound (3.58 g, Rf=0.45: thin layer chromatography on silica gel usinghexane:ethyl acetate=1:1 as the eluant) which was allowed to stand atroom temperature to give a solid (mp 74-76° C.).

EXAMPLE 27

[0690]3-[4-(6-Methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylthiopropionicAcid Hydrochloride (Hydrochloride of Exemplification Compound Number5-4)

[0691] To a solution of ethyl3-[4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylthiopropionate(2.0 g) in tetrahydrofuran (25 ml) were added successively potassiumhydroxide monohydrate (0.42g), and dimethylformamide (5 ml). The mixturewas stirred at room temperature for 2 hours. After addition of potassiumhydroxide (0.42 g) and water (5 ml) the mixture was stirred at roomtemperature for 20 minutes. And then after addition of dimethylformamide(5 ml) the mixture was further stirred at room temperature for 1 hourand allowed to stand over night. To the reaction mixture was furtheradded potassium hydroxide (0.42 g), water (5 ml) and dimethylformamide(5 ml) and the the mixture was stirred at 75° C. for 8 hours. Thereaction mixture was poured into 1N hydrochloric acid (800 ml), stirredfor 30 minutes and filtrated to give crystals. The crystals were washedsuccessively with water, acetone and ethyl acetate and dried underreduced pressure to afford the title compound (1.27 g, mp 201-206° C.).

EXAMPLE 28

[0692]3-[4-(6-Methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylthiopropionicAmide (Amide of Exemplification Compound Number 5-4)

[0693] To a mixture of3-[4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylthiopropionicacid (1.1 g), tetrahydrofuran (15 ml) and dimethylformamide (15 ml) wereadded successively triethylamine (0.82 ml) and ethyl chloroformate (0.28ml). The mixture was stirred at room temperature for 30 minutes. Afteraddition of aqueous ammonia solution (5 ml, 28%) the mixture was stirredat room temperature for 15 minutes and allowed to stand overnight. Thesolvent of the reaction mixture was evaporated under reduced pressure.The residue was partitioned between ethyl acetate and water. The extractwas washed with saturated aqueous sodium chloride solution and driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was washed with ethyl acetate and thenrecrystallized from a mixture of ethanol and ethyl acetate to afford thetitle compound (0.45 g, mp 204-206° C.).

EXAMPLE 29

[0694]3-[4-(6-Methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylsulfenylpropionicAmide (Amide of Exemplification Compound Number 5-21) and

[0695]3-[4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylsulfonylpropionicAmide (Amide of Exemplification Compound Number 5-22)

[0696]3-[4-(6-Methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylthiopropionicamide (0.35 g) was added to sulfolane (8 ml) and methylene chloride (15ml). To the mixture was added successively sodium hydrogencarbonate (84mg) and m-chloroperoxybenzoic acid (0.22 g). This mixture was stirred atroom temperature for 1.5 hours. Aqueous sodium sulfate solution (5 ml,2%) was added to the reaction mixture and the mixture was stirred atroom temperature for 10 minutes. The mixture was partitioned betweenethyl acetate and water. The extract was washed with saturated aqueoussodium chloride solution, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was chromatographed ona LiChroprepNH2 (Merck) column using ethanol:ethyl acetate=1:15 as theeluant to give the title compounds (3.93 g, Rf=0.45: thin layerchromatography on a silica gel plate (LiChroprepNH2 (Merck)) usinghexane:ethyl acetate=1:5 as the eluant) as crystals. The crystals wererecrystallized from a mixture of ethanol and ethyl acetate to afford3-[4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylsulfenylpropionicamide (0.14 g, mp 188-190° C.) and3-[4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylsulfonylpropionicamide (0.12 g, mp 233-236° C.).

EXAMPLE 30

[0697] 3-[4-[6-(β-D-Glucopyranosyloxyuronicacid)-1-methyl-1H-benzimidazol-2-ylmethoxy]phenyl]-2-methylthiopropionicAmide (Amide of Exemplification Compound Number 5-48)

[0698]5-[4-[6-Methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dionehydrochloride (5 mg/kg) was orally administered to a rat and bileobtained from the rat was collected from 0 through 24 hours. The bilewas lyophylized and the residue was chromatographed on an ODS column(packing agent: ODS-A 120-S-75 a product of YMS Co., Ltd.) using agradient elution of water (pH 4 prepared with 1 mol/ml hydrochloricacid):acetonitrile=100:0 to 60:40 as the eluant to give a crudemetabolite. The crude metabolite was further purified by HPLC to affordthe title compound (m/z 548 [M+H]⁺ EIS-MS; Q-TOF hybrid-type MS/MSspectrometer (a product of Micromass UK Co.)).

[0699] The HPLC conditions (gradient method)

[0700] HPLC devices: Hitachi HPLC gradient system (L-6200 IntelligentPump, D-2500

[0701] Chromato-Integrator, L-4000 UV-detector)

[0702] column: YMC-Pack ODS-A A-312 (length 150 mm, internal diameter6.0 mm, particle diameter 5 μm, a product of YMC Co., Ltd.)

[0703] flow rate: 1.0 ml/min

[0704] temperature: room temperature

[0705] retention time: 13.9 minutes

[0706] mobile phase: mobile phase A: water (0.01% trifluoroacetic acidsolution)

[0707]  mobile phase B: acetonitrile (0.01% trifluoroacetic acidsolution)

[0708] gradient elution conditions:

[0709] 0 min mobile phase A 88%, mobile phase B 12%

[0710] 30 min mobile phase A 40%, mobile phase B 60%

[0711] 35 min mobile phase A 10%, mobile phase B 90%

[0712] 40 min mobile phase A 10%, mobile phase B 90%

[0713] detection: UV detection: detection wave length 220 nm

[0714] RI detection: ¹⁴C detection

[0715] detector: Flow-one/beta-Radiomatic525TR (a product of PackardCo., Ltd.)

[0716] liquid scintillator: ULTIMA-FLO M (a product of Packard Co.,Ltd.)

[0717] flow rate: 3.0 ml/min

EXAMPLE 31

[0718]3-[4-(6-Methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylsulfenylpropionicAmide (Amide of Exemplification Compound Number 5-21)

[0719] The title compound (m/z 403 [M+H] (EIS-MS; Q-TOF hybrid-typeMS/MS spectrometer (a product of Micromass UK Co.)), retention time 18.2minutes) was obtained by a similar procedure to that described inExample 30.

EXAMPLE 32

[0720]3-[4-(6-Hydroxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylthiopropionicAmide (Amide of Exemplification Compound Number 5-26)

[0721] The title compound (m/z 372 [M+H]⁺ (EIS-MS; Q-TOF hybrid-typeMS/MS spectrometer (a product of Micromass UK Co.)), retention time 18.2minutes) was obtained by a similar procedure to that described inExample 30.

Example 33

[0722]3-[4-[6-Methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy]phenyl]-2-methylsulphenylpropionicamide (Amide of Exemplification Compound Number 5-21)

[0723]5-[4-[6-Methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dionehydrochloride (5 mg/kg) was orally administered to a rat and urineobtained from the rat was collected from 0 through 24 hours. The urinewas lyophylized and the residue was chromatographed on an ODS column(packing agent: ODS-A 120-S-75 a product of YMS Co., Ltd.) using agradient elution of water (pH 4 prepared with 1 mol/ml hydrochloricacid):acetonitrile=100:0 to 60:40 as the eluant to give a crudemetabolite. The crude metabolite was further purified by HPLC to affordthe title compound (m/z 402 [M+H]⁺ (EIS-MS; Q-TOF hybrid-type MS/MSspectrometer (a product of Micromass UK Co.))).

[0724] The HPLC conditions (gradient method)

[0725] HPLC devices: Hitachi HPLC gradient system (L-6200 IntelligentPump, D-2500

[0726] Chromato-Integrator, L-4000 UV-detector)

[0727] column: YMC-Pack ODS-A A-312 (length 150 mm, internal diameter6.0 mm, diameter of particle 5 μm, a product of YMC Co., Ltd.)

[0728] flow rate: 1.0 ml/min

[0729] temperature: room temperature

[0730] retention time: 17.2 minutes

[0731] mobile phase: mobile phase A: water (0.01% trifluoroacetic acidsolution)

[0732]  mobile phase B: acetonitrile (0.01% trifluoroacetic acidsolution)

[0733] gradient elution conditions:

[0734] 0 min mobile phase A 88%, mobile phase B 12%

[0735] 30 min mobile phase A 40%, mobile phase B 60%

[0736] 35 min mobile phase A 10%, mobile phase B 90%

[0737] 40 min mobile phase A 10%, mobile phase B 90%

[0738] detection: UV detection: detection wave length 220 nm

[0739] RI detection: ¹⁴C detection

[0740] detector: Flow-one/beta-Radiomatic525TR (a product of PackardCo., Ltd.)

[0741] liquid scintillator: ULTIMA-FLO M (a product of Packard Co.,Ltd.)

[0742] flow rate: 3.0 ml/min

EXAMPLE 34

[0743]3-[4-(6-Methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylsulphenylpropionicAmide (Exemplification Compound Number 5-21)

[0744] The title compound (m/z 403 [M+H]⁺ (EIS-MS; Q-TOF hybrid-typeMS/MS spectrometer (a product of Micromass UK Co.)), retention time 18.3minutes) was obtained by a similar procedure to that described inExample 33.

EXAMPLE 35

[0745] 3-[4-[6-(β-D-Glucopyranosyloxyuronicacid)-1-methyl-1H-benzimidazol-2-ylmethoxy]phenyl]-2-mercaptopropionicAcid Hydrochloride (Hydrochloride of Exemplification Compound Number5-45)

[0746] An aqueous solution of potassium hydroxide is added to asuspension of1-O-[1-methyl-2-[4-(2,4-thiazolidinedione-5-ylmethyl)phenoxymethyl]-1H-benzimidazol-2yl]-β-D-glucopyranosyloxyuronicacid in ethanol and the mixture is stirred. The reaction mixture ispoured into ice-water and acidified with hydrochloric acid. This mixtureis stirred and the precipitate is filtered and dried under reducedpressure to afford the title compound.

EXAMPLE 36

[0747] Ethyl3-[4-(6-hydroxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylthiopropionateHydrochloride (Ethyl Ester Hydrochloride of Exemplification CompoundNumber 5-26)

[0748] A mixture of t-butylN-{2-[4(2-methylthio-2-ethoxycarbonylethyl)phenoxyacetylamino]-5-hydroxyphenyl}-N-methylcarbamate(11 g), ethanol (50 ml) and 4N-hydrogen chloride/dioxane (200 ml) wasallowed to stand at room temperature. The solvent of the reactionmixture was evaporated and the residue was filtered to give aprecipitate which was washed with ethyl acetate to afford the titlecompound (6.12 g, mp 149-152° C.) as a grayish white powder.

EXAMPLE 37

[0749]3-[4-(6-Hydroxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylthiopropionicAcid Hydrochloride (Hydrochloride of Exemplification Compound Number5-26)

[0750] The title compound (2.7 g, mp 195-198° C., pale red powder) wasobtained by a similar procedure to that described in Example 27 usingethyl3-[4-(6hydroxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylthiopropionatehydrochloride (6 g), potassium hydroxide (6 g), N,N-dimethylformamide(50 ml) and distilled water (50 ml).

EXAMPLE 38

[0751]2-Mercapto-3-[4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]propionicAmide (Amide of Exemplification Compound Number 5-1)

[0752] A mixture of2-acetylthio-3-[4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]propionicacid (1.53 g), anhydrous triethylamine (0.4 g), chloroethylformate (0.65g), anhydrous tetrahydrofuran (10 ml) and anhydrousN,N-dimethylformamide (10 ml) was stirred at room temperature for 1hour. An aqueous solution of ammonia (20 ml, 28%) was added to thereaction mixture and this mixture was stirred for 2 hours and thenallowed to stand overnight. The reaction mixture was partitioned betweenethyl acetate and water. The extract was washed with saturated aqueoussodium chloride solution and dried over anhydrous magnesium sulfate andthen concentrated. The residue was purified by liquid chromatography(LiChroprepNH2 (Merck)) using ethanol:ethyl acetate=1:12 as the eluantto afford the title compound (0.21 g, mp 204-208° C.) as a pale yellowpowder.

EXAMPLE 39

[0753] Methyl3-[4-(1methyl-6-methylthio-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylthiopropionateHydrochloride (Methyl Ester Hydrochloride of Exemplification CompoundNumber 5-67)

[0754] A mixture of methyl3-[4-(1-methyl-6methylthio-1H-benzimidazol-2-ylmethoxy)phenyl]-2-mercaptopropionate(7.14 g), methyl iodide (3.78 g), triethylamine (2.69 g), and anhydroustetrahydrofuran (200 ml) was stirred at room temperature for 23 hours.The reaction mixture was concentrated and partitioned between ethylacetate and water. The extract was dried over anhydrous sodium sulfateand then concentrated. The residue was chromatographed on a silica gelcolumn using hexane:ethyl acetate=1:2 as the eluant and the product wastreated with 4N hydrogen chloride/ethyl acetate to afford the titlecompound (5.75 g, mp 163-166° C.).

EXAMPLE 40

[0755]3-[4-(1-Methyl-6-methylthio-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylthiopropionicAcid Hydrochloride (Hydrochloride of Exemplification Compound Number5-67)

[0756] A mixture of methyl3-[4-(1-methyl-6-methylthio-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylthiopropionatehydrochloride (5.75 g), concentrated hydrochloric acid (100 ml) and1,4-dioxane (100 ml) was heated at reflux for 90 minutes. The reactionmixture was concentrated to dryness. To the residue was addedtetrahydrofuran and the mixture was irradiated with ultrasonic waves.The insoluble material was isolated by filtration, washed with ethylacetate, dissolved in N,N-dimethylformamide and reprecipitated withether to afford the title compound (5.02 g, mp 193-196° C.).

EXAMPLE 41

[0757] Methyl3-[4-(1-methyl-6-methylthio-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylthiopropionate(Methyl Ester of Exemplification Compound Number 5-67)

[0758] Crude 2-(N-t-butoxycarbonyl-N-methylamino)-4-methylthioaniline(54.8 g, Rf=0.16: thin layer chromatography on a silica gel plate usinghexane:ethyl acetate=3:1 as the eluant) was obtained by a similarprocedure to that described in Reference example 5 using2-(N-t-butoxycarbonyl-N-methylamino)-4-methylthionitrobenzene (55.9 g),palladium on carbon (7.25 g, 10%) and a mixture ofmethanol:1,4-dioxane=1:1 (600 ml).

[0759] A mixture of2-(N-t-butoxycarbonyl-N-methylamino)-4-methylthioaniline (54.8 g),4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid (64.0 g), diethylcyanophosphonate (36.8 g), triethylamine (22.8 g) and anhydroustetrahydrofuran (300 ml) was stirred for 67 hours at room temperature.The reaction mixture was concentrated and water was added to theresidue. The mixture was neutralized with 3N hydrochloric acid andsodium bicarbonate and extracted with ethyl acetate. The extract wasdried over anhydrous sodium sulfate and concentrated. The residue wasdissolved in 4N hydrogen chloride/dioxane (150 ml) and the solution wasstirred at room temperature for 15 hours and then at 80° C. for 5 hours.The reaction mixture was concentrated, neutralized with sodiumbicarbonate and extracted with a mixture of tetrahydrofuran and ethylacetate. The extract was dried over anhydrous sodium sulfate. Thesolvent of the extract was evaporated and the residue was reprecipitatedusing N,N-dimethylformamide and ethyl acetate to give a precipitate. Theprecipitate was suspended in 4N hydrogen chloride/ethyl acetate andinsoluble material was obtained by filtration which was washed withethyl acetate and dried in the air to give the desired intermediate.

[0760] A solution of the intermediate (35.2 g) in water (200 ml) and amethanolic solution of sodium methoxide (300 ml, 28%) was stirred at 80°C. for 90 minutes. The reaction mixture was concentrated and acidifiedwith 6N hydrochloric acid to give a precipitate. The precipitate wascollected by filtration, successively washed with water and ethylacetate and then dried under reduced pressure to afford the desiredproduct.

[0761] A mixture of the product (22.4 g), 4N hydrogen chloride/dioxane(150 ml) and methanol (150 ml) was stirred at room temperature for 65hours. The reaction mixture was concentrated, neutralized with aqueoussodium bicarbonate solution (5%) and extracted with ethyl acetate. Theextract was dried over anhydrous sodium sulfate and then concentrated.The residue was chromatographed on a silica gel column usinghexane:ethyl acetate=1:3 as the eluant to afford the title compound(7.49 g, mp 97-100° C.).

REFERENCE EXAMPLE 1

[0762] Methyl 4-(t-butoxycarbonylmethoxy)phenyllactate

[0763] A mixture of methyl 4-hydroxyphenyllactate (18.5 g), t-butylbromoacetate (14 ml), anhydrous potassium carbonate (26.0 g) andanhydrous dimethylformamide (300 ml) was stirred at 60° C. for 10 hoursand then allowed to stand at room temperature overnight The reactionmixture was partitioned between ethyl acetate and water. The extract waswashed with saturated aqueous sodium chloride solution, dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresidue was chromatographed on a silica gel column using hexane:ethylacetate=2:1-1:1 as the eluant to afford the title compound (17.5 g,Rf=0.62: thin layer chromatography on a silica gel plate usinghexane:ethyl acetate=1:1 as the eluant).

REFERENCE EXAMPLE 2

[0764] Methyl3-[4-(t-butoxycarbonylmethoxy)phenyl]-2-(4-fluorobenzyloxy)propionate

[0765] A mixture of methyl 4-(t-butoxycarbonylmethoxy)phenyllactate (3.0g), 4-fluorobenzylbromide (2.4 ml), silver oxide (9.0 g) and toluene (60ml) was stirred at 80° C. under a nitrogen atmosphere for 3 hours. Thereaction mixture was filtered and the filtrate was concentrated underreduced pressure. The residue was chromatographed on a silica gel columnusing hexane:ethyl acetate=5:1 as the eluant to afford the titlecompound (2.9 g, Rf=0.39: thin layer chromatography on a silica gelplate using hexane:ethyl acetate=3:1 as the eluant).

REFERENCE EXAMPLE 3

[0766] Methyl3-[4-(carboxymethoxy)phenyl]-2-(4-fluorobenzyloxy)propionate

[0767] A solution of methyl3-[4-(t-butoxycarbonylmethoxy)phenyl]-2-(4-fluorobenzyloxy)propionate(2.8 g) in 4N hydrogen chloride/dioxane (50 ml) was stirred at roomtemperature for 3 hours. The reaction mixture was concentrated underreduced pressure to afford the title compound (2.42 g, Rf=0.10: thinlayer chromatography on a silica gel plate using hexane:ethylacetate=5:1 as the eluant).

REFERENCE EXAMPLE 4

[0768]4-(4-(Adamantan-1-ylphenoxy)-2-(N-t-butoxycarbonyl-N-methylamino)nitrobenzene

[0769] After washing sodium hydride (2.1 g) with hexane,dimethylformamide (200 ml) was added it. In an ice bath4-(1-adamantyl)phenol (10 g) was added and this mixture was stirred atroom temperature for 1 hour. To this reaction mixture was added4-chloro-2-(N-t-butoxycarbonyl-N-methylamino)nitrobenzene (15.1 g) in anice bath. The mixture was stirred at room temperature for 2 hours andthen allowed to stand at room temperature 2 days. The dimethylformamidewas evaporated under reduced pressure. The residue was partitionedbetween ethyl acetate and water. The extract was washed with saturatedaqueous sodium chloride solution, dried over anhydrous sodium sulfateand concentrated under reduced pressure. The residue was chromatographedon a silica gel column using hexane:ethyl acetate=10:1 as the eluant toafford the title compound (23.0 g, Rf=0.63: thin layer chromatography ona silica gel plate using hexane:ethyl acetate=3:1 as the eluant).

REFERENCE EXAMPLE 5

[0770]4-(4-Adamantan-1-ylphenoxy)-2-(N-t-butoxycarbonyl-N-methylamino)aniline

[0771] A mixture of4-(4-adamantan-1-ylphenoxy)-2-(N-t-butoxycarbonyl-N-methylamino)nitrobenzene(14 g), palladium on carbon (1.50 g, 10%) and methanol (300 ml) wasstirred at room temperature under a hydrogen atmosphere for 2 hours andthen 50° C. for 2 hours, allowed to stand at room temperature overnightand then stirred at 50° C. for 2 hours. The insoluble material of thereaction mixture was filtered and the filtrate was concentrated underreduced pressure. The residue was chromatographed on a silica gel columnusing hexane:ethyl acetate=3:1 as the eluant to afford the titlecompound (6.70 g, mp 85-90° C.).

REFERENCE EXAMPLE 6

[0772] Methyl3-{4-[4-(4-adamantan-1-ylphenoxy)-2-(N-t-butoxycarbonyl-N-methylamino)phenylaminocarbonylmethoxy]phenyl}-2-4-fluorobenzyloxy)propionate

[0773] Diethyl cyanophosphonate (0.30 ml) was added to a solution ofmethyl 3-[4-(carboxymethoxy)phenyl]-2-(4-fluorobenzyloxy)propionate (0.6g),4-(4-adamantan-1-ylphenoxy)-2-(N-t-butoxycarbonyl-N-methylamino)aniline(0.75 g) and triethylamine (0.28 ml) in tetrahydrofuran (15 ml). Themixture was stirred at room temperature for 5 hours. The reactionmixture was partitioned between ethyl acetate and water. The extract waswashed with saturated aqueous sodium chloride solution, dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresidue was chromatographed on a silica gel column using hexane:ethylacetate=3:1 as the eluant to afford the title compound (1.08 g, mp52-56° C.).

REFERENCE EXAMPLE 7

[0774]4-(3,5-Di-t-butyl-4-hydroxyphenylthio-2-(N-t-butoxycarbonyl-N-methylamino)nitrobenzene

[0775] A mixture of 3,5-di-t-butyl-4-hydroxyphenylmercaptane (8.0 g),4-chloro-2-(N-t-butoxycarbonyl-N-methylamino)nitrobenzene (9.62 g),potassium carbonate (23.2 g) and dimethylformamide (150 ml) was stirredat 80° C. for 1 hour. The dimethylformamide was evaporated under reducedpressure. The residue was partitioned between ethyl acetate and water.The extract was washed with saturated aqueous sodium chloride solution,dried over anhydrous sodium sulfate and concentrated under reducedpressure. The residue was chromatographed on a silica gel column usinghexane:ethyl acetate=20:1-10:1 as the eluant to afford the titlecompound (12.1 g, mp 140-141° C.).

REFERENCE EXAMPLE 8

[0776]4-(3,5-Di-t-butyl-4-hydroxyphenylthio)-2-(N-t-butoxycarbonyl-N-methylamino)aniline

[0777] The title compound (8.82 g, mp 95-96° C.) was obtained by asimilar procedure to that described in Reference example 5 using4-(3,5-di-t-butyl-4-hydroxyphenylthio)-2-(N-t-butoxycarbonyl-N-methylamino)nitrobenzene(9.4 g), palladium on carbon (9.4 g, 10%) and methanol (100 ml).

REFERENCE EXAMPLE 9

[0778] Methyl3-{4-[4-(3,5-di-t-butyl-4-hydroxyphenylthio)-2-(N-t-butoxycarbonyl-N-methylamino)phenylaminocarbonylmethoxy]phenyl}-2-(4-fluorobenzyloxy)propionate

[0779] The title compound (0.60 g, Rf=0.48: thin layer chromatography ona silica gel plate using hexane:ethyl acetate=3:1 as the eluant) wasobtained by a similar procedure to that described in Reference example 6using4-(3,5-di-t-butyl-4-hydroxyphenylthio)-2-(N-t-butoxycarbonyl-N-methylamino)aniline(2.28 g), methyl3-[4-(carboxymethoxy)phenyl]-2-(4-fluorobenzyloxy)propionate (1.75 g),triethylamine(0.83 ml), tetrahydrofuran (50 ml) and diethylcyanophosphonate (0.90 ml).

REFERENCE EXAMPLE 10

[0780] 4-(5,5-Dimethyl-2-oxodioxolan-3-ylmethyl)phenol

[0781] Concentrated sulfuric acid (10 ml) was added dropwise to asolution of 4-hydroxyphenyllactic acid (30 g) in acetone (30 ml) at −50°C. and the mixture was stirred at room temperature for 4 hours. Thereaction mixture was poured into ice-water and neutralized with aqueoussodium hydroxide solution and aqueous sodium hydrogencarbonate solutionand extracted with ethyl acetate. The extract was washed with saturatedaqueous sodium chloride solution, dried over anhydrous sodium sulfateand concentrated to afford the title compound (21.6 g, Rf=0.34: thinlayer chromatography on a silica gel plate using hexane:ethylacetate=4:1 as the eluant).

REFERENCE EXAMPLE 11

[0782] Benzyl 4-(5,5-dimethyl-2-oxodioxolan-3-ylmethyl)phenoxyacetate

[0783] A mixture of 4-(5,5-dimethyl-2-oxodioxolan-3-ylmethyl)phenol(21.5 g), benzyl bromoacetate (44 g), cesium carbonate (63 g) andacetone (500 ml) was stirred at room temperature for 1.5 hours. Thesolvent of the reaction mixture was evaporated under reduced pressure.The residue was partitioned between ethyl acetate and water. The extractwas washed with saturated aqueous sodium chloride solution, dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresidue was chromatographed on a silica gel column using hexane:ethylacetate=5:1-3:1 as the eluant to afford the title compound (32.9 g,Rf=0.51: thin layer chromatography on a silica gel plate usinghexane:ethyl acetate=4:1 as the eluant).

REFERENCE EXAMPLE 12

[0784] 4-(5,5-Dimethyl-2-oxodioxolan-3-ylmethyl)phenoxyacetic Acid

[0785] A mixture of benzyl4-(5,5-dimethyl-2-oxodioxolan-3-ylmethyl)phenoxyacetate (15 g),palladium on carbon (2 g, 5%) and dioxane (150 ml) was stirred at roomtemperature under a hydrogen atmosphere for 1.5 hours. The insolublematerial of the reaction mixture was filtered and the filtrate wasconcentrated under reduced pressure. The residue was filtered and washedwith diisopropyl ether and dried to afford the title compound (9.42 g,mp 138-139° C.).

REFERENCE EXAMPLE 13

[0786]4-(5,5-Dimethyl-2-oxodioxolan-3-ylmethyl)phenoxyacetyl-N-[2-(N-t-butoxycarbonyl-N-methylamino)-4-methoxyphenyl]amide

[0787] The title compound (4.56 g, Rf=0.17: thin layer chromatography ona silica gel plate using hexane:ethyl acetate=3:1 as the eluant) wasobtained by a similar procedure to that described in Reference example 6using 2-(N-t-butoxycarbonyl-N-methylamino)-4-methoxyaniline (2.5 g),4-(5,5-dimethyl-2-oxodioxolan-3-ylmethyl)phenoxyacetic acid (3.0 g),triethylamine (1.66 ml), tetrahydrofuran (100 ml) and diethylcyanophosphonate (1.82 ml).

REFERENCE EXAMPLE 14

[0788] 4-Methoxymethoxy-2,3,5-trimethylphenol

[0789] Sodium hydride (8.51 g, 55% suspension in mineral oil) was addedto a solution of 4-hydroxy-2,3,5-trimethylphenol pivalate (35.4 g) intetrahydrofuran (300 ml) at room temperature. The mixture was stirredfor 30 minutes. To the reaction mixture was added dropwise methoxymethylchloride (15.7 g). This mixture was stirred at room temperature for 1hour. The solvent of the reaction mixture was evaporated under reducedpressure. The residue was partitioned between ethyl acetate and water.The organic extract was dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The residue was dissolved inmethanol (100 ml) and to this solution was added dropwise a solution ofpotassium hydroxide (16.8 g) in methanol (100 ml). The mixture wasstirred at room temperature and concentrated under reduced pressure. Theresidue was neutralized with 3N hydrochloric acid and extracted withethyl acetate. The extract was dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The residue was chromatographed ona silica gel column using hexane:ethyl acetate=5:1 as the eluant toafford the title compound (27.5 g, Rf=0.16: thin layer chromatography ona silica gel plate using hexane:ethyl acetate=4:1 as the eluant).

REFERENCE EXAMPLE 15

[0790]2-(N-t-Butoxycarbonyl-N-methylamino)-4-(methoxymethoxy-2,3,6-trimethylphenoxy)nitrobenzene

[0791] Sodium hydride (6.11 g, 55% suspension in mineral oil) was addedto a solution of 4-methoxymethoxy-2,3,5-trimethylphenol (27.5 g) indimethylformamide (300 ml). After stirring the mixture for 1 hour4chloro-2-(N-t-butoxycarbonyl-N-methylamino)nitrobenzene (40.1 g) wasadded in small portions to the mixture and stirred at 120° C. for 2hours. The solvent of the reaction misture was evaporated under reducedpressure. The residue was partitioned between ethyl acetate and water.The extract was dried over anhydrous sodium sulfate and concentratedunder reduced pressure. The residue was chromatographed on a silica gelcolumn using hexane: ethyl acetate=5:1 as the eluant to afford the titlecompound (57.0 g, Rf=0.55 : thin layer chromatography on a silica gelplate using hexane : ethyl acetate=4:1 as the eluant).

[0792] Reference example 16

[0793]2-(N-t-Butoxycarbonyl-N-methylamino)-4-(4-methoxymethoxy-2,3,6-trimethylphenoxy)aniline

[0794] The title compound (52.5 g, Rf=0.31 : thin layer chromatographyon a silica gel plate using hexane : ethyl acetate=3:1 as the eluant)was obtained by a similar procedure to that described in Referenceexample 5 using 2-(N-t-butoxycarbonyl-N-methylamino)-4-(4-methoxymethoxy-2,3,6-trimethylphenoxy)nitrobenzene (57.0 g),palladium on carbon (3 g, 10%) and methanol (500 ml).

[0795] Reference example 17

[0796]4-(5,5-Dimethyl-2-oxodioxolan-3-ylmethyl)phenoxyacetyl-N-[2-(N-t-butoxycarbonyl-N-methylamino)-4-(4-methoxymethoxy-2,3,5-trimethylphenoxy)phenyl]amide

[0797] The title compound (6 g, Rf=0.25 : thin layer chromatography on asilica gel plate using hexane : ethyl acetate=3:1 as the eluant) wasobtained by a similar procedure to that described in Reference example 6using 2-(N-t-butoxycarbonyl-N-methylamino)-4-methoxymethoxy-2,3,6-trimethylphenoxy)aniline (4.0 g),4-(5,5-dimethyl-2-oxodioxolan-3-ylmethyl)phenoxyacetic acid (3.23 g),triethylamine (1.73 ml), tetrahydrofuran (150 ml) and diethylcyanophosphonate (1.9 ml).

[0798] Reference example 18

[0799]4-(5,5-Dimethyl-2-oxodioxolan-3-ylmethyl)phenoxyacetyl-N-[2-(N-t-butoxycarbonyl-N-methylamino)-4-(3,5-di-t-butyl-4-hydroxyphenylthio)pheny]amide

[0800] The title compound (5.15 g, Rf=0.38 : thin layer chromatographyon a silica gel plate using hexane : ethyl acetate=2:1 as the eluant)was obtained by a similar procedure to that described in Referenceexample 6 using 4-(3,5-di-t-butyl-4-hydroxyphenylthio)-2-(N-t-butoxycarbony-N-methylamino)aniline (4.5 g),4-(5,5-dimethyl-2-oxodioxolan-3-ylmethyl) phenoxyacetic acid (3.0 g),triethylamine (1.66 ml), tetrahydrofuran (100 ml) and diethylcyanophosphonate (1.82 ml).

[0801] Reference example 19

[0802] Methyl2-axido-3-[4-(6-methoxy-1-methyl-1H-benzimidazole-2-yl)phenyl]propionate

[0803] A mixture of methyl4-(1-methyl-6-methoxy-1H-benzimidazole-2-yl-methoxy) phenyllactate (2.5g), diphenylphosphoryl azide (2.3 ml), diethyl azodicatboxylate (4.8ml), triphenylphosphine (2.8 g) and tetrahydrofuran (100 ml) was stirredat room temperature for 1 hour and then allowed to stand overnight. Thesolvent of the reaction mixture was evaporated under reduced pressure.The residue was chromatographed on a silica gel column using hexane :ethyl acetate=2:1 as the eluant to afford the title compound (2.1 g, mp105-107° C.).

[0804] Reference example 20

[0805] N-(2-Benzoylphenyl)tyrosine methyl ester

[0806] A mixture of tyrosine methyl ester hydrochloride (4.8 g),2-benzoylcyclohexanone (5.0 g), palladium on carbon (1.0 g, 10%),triethylamine (2.9 ml) and anisole (70 ml) was heated at reflux for 20hours. The reaction mixture was filtered and the filtrate waspartitioned between ethyl acetate and water. The extract was washed withsaturated aqueous sodium chloride solution, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas chromatographed on a silica gel column using hexane : ethylacetate=3:1 as the eluant to afford the title compound (1.83 g, Rf=0.39: thin layer chromatography on a silica gel plate using hexane : ethylacetate=3:1 as the eluant).

[0807] Reference example 21

[0808] 4-t-Butoxycarbonylmethoxy-N-(2-benzoylphenyl)alanine methyl ester

[0809] A mixture of N-(2-benzoylphenyl)tyrosine methyl ester (0.97 g),t-butyl bromoacetate (0.55 ml), cesium carbonate (1.14 g), and acetone(15 ml) was stirred at room temperature for 1.5 hours and allowed tostand overnight. The reaction mixture was partitioned between ethylacetate and water. The extract was washed with saturated aqueouschloride solution, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure to afford the title compound (1.42g, Rf=0.65 : thin layer chromatography on a silica gel plate usinghexane : ethyl acetate=3:1 as the eluant).

[0810] Reference example 22

[0811] 4-Carboxymethoxy-N-(2-benzoylphenyl)alanine methyl ester

[0812] A mixture of 4-t-butoxycarbonylmethoxy-N-(2-benzoylphenyl)alaninemethyl ester (1.4 g), 4N hydrogen chloride/dioxane (10 ml) and dioxane(10 ml) was stirred at room temperature for 3 hours and allowed to standovernight. The reaction mixture was concentrated under reduced pressure.To the residue was added toluene and the mixture was concentrated underreduced pressure. The residue was chromatographed on a silica gel column(LiChroprepDIOL (Merck)) using hexane : ethyl acetate=2:1−1:1 as theeluant to afford the title compound (0.87 g, Rf=0.53 : thin layerchromatography on a silica gel plate using hexane : ethyl acetate=3:2 asthe eluant).

[0813] Reference example 23

[0814]2-(N-t-Butoxycarbonyl-N-methylamino)-4-(4-amino-3,5-dimethylphenoxy)nitrobenzene

[0815] 4-Amino-3,5-dimethylphenol (1.10 g) was added to a suspension ofsodium hydride (0.35 g, 55% (w/w) dispersion in mineral oil) inanhydrous N,N-dimethylformamide and the mixture was stirred at roomtemperature for 15 minutes. To the mixture was added in small portions4-chloro-2-(N-t-butoxycarbonyl-N-methylamino)-nitrobenzene and themixture was stirred at 120° C. for 1 hour. The reaction mixture wasconcentrated and the residue was partitioned between ethyl acetate andwater The extract was dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The residue was chromatographed ona silica gel column using hexane : ethyl acetate=3:1 the eluant toafford the title compound (2.27 g, Rf=0.24 : thin layer chromatographyon a silica gel plate using hexane : ethyl acetate=3:1 as the eluant).

[0816] Reference 24

[0817]2-(N-t-Butoxycarbonyl-N-nehtylamino)-4-(4-t-butoxycarbonylamino-3,5-dimethylphenoxy)nitrobenzene

[0818] A mixture of2-(N-t-butoxycarbonyl-N-methylamino)-4-(4-amino-3,5-dimethylphenoxy)nitrobenzene (2.27 g), di-t-butylcarbonate (1.28 g),triethylamine (0.59g) and anhydrous tetrahydrofuran (20 ml) was heated at reflux for 6hours. The reaction mixture was concentrated and the residue waspartitioned between ethyl acetate and water. The extract was dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresidue was chromatographed on a silica gel column using hexane : ethylacetate=10:1 as the eluant to afford the title compound (1.74 g, mp154-156° C. ).

[0819] Reference example 25

[0820]2-(N-t-Butoxycarbonyl-N-methylamino)-4-(4-t-butoxycarbonylamino-3,5-dimethylphenoxy)aniline

[0821] The title compound (1.56 g, Rf=0.14 : thin layer chromatographyon a silica gel plate using hexane : ethyl acetate=3:1 as the eluant)was obtained by a similar procedure to that described in Referenceexample 5 using 2-(N-t-butoxycarbonyl-N-methylamino)-4-(4-t-butoxycarbonylamino-3,5-dimethylphenoxy)nitrobenzene (1.71 g), 6g, Rf=0.14 : thin layer chromatography on a silica gel 32 3:1 as theeluant) was obtained by a similar procedure to that described inReference example 5 using 2-(N-t-butoxycarbonyl-N-methylamino)-4-(4-t-butoxycarbonylamino-3,5-dimethylphenoxy)nitrobenzene (1.71 g),palladium on carbon (0.2 g, 10%) and methanol (100 ml).

[0822] Reference example 264-[N-t-Butoxycarbonyl-N-methylamino)-4-(4-t-butonycarbonylamino-3,5-dimethylphenoxy)phenylaminocarbonylmethoxy]-N-(2-benzoylphenyl)phenylalanine methylester

[0823] The title compound (1.06 g, Rf=0.93 : thin layer chromatographyon a silica gel plate using ethyl acetate as the eluant) was obtained bya similar procedure to that described in Reference example 6 using2-(N-t-butoxycarbonyl-N-methylamino)-4-(4-t-butoxycarbonylamino-3,5-dimethylphenoxy)aniline(0.69 g), 4-carboxymethoxy-N -(2-benzoylphenyl)alanine methyl ester(0.85 g), triethylamine (0.3 ml), pg,197 tetrahydrofuran (20 ml) anddiethyl cyanophosponate (0.33 ml).

[0824] Reference example 27

[0825]1-O-[1-Methyl-2-[4-(2,4-thiazolidinedione-5-ylmethyl)phenoxymethyl]-1H-benzimidazol-2-yl]-β- D-glucopyranosyloxyuronic acid

[0826] A mixture of5-[4-(6-hydroxy-1-methyl-1H-benzimidazol-2-ylmethoxy)benzyl]thizolidin-2,4-dione hydrochloride,1,2,3,4-tetra-O-acetyl-β-D-pyranuronic acid methyl ester,toluenesulfonic acid and nitrobenzene was stirred under reduced pressurein a heating bath. The solvent of the reaction mixture was evaporatedunder reduced pressure. The residue was chromatographed on a column togive the desired compound having protecting groups. An aqueous solutionof sodium hydroxide was added dropwise to solution of the product inmethanol in an ice bath and the mixture was stirred. The reactionmixture was saturated with sodium chloride, acidified with hydrochloricacid and extracted with ethyl acetate. The ethyl acetate was evaporatedand the residue was purified by chromatography on a column to afford thetitle compound.

[0827] Example 28

[0828]5-[4-(6-Hydroxy-1-methyl-1H-benzimidazol-2-ylmethoxy)benzyl]thiazolidine-2,4-dionehydrochloride

[0829] A mixture of t-butylN-(2-amino-5-hydroxyphenyl)-N-methylcarbamate (0.43 g),5-(4-carboxymethoxybenzyl)thiazolidine-2,4-dione (0.51 g), diethylcyanophosphaonate (0.29 g) triethylamine (0.18 g) and tetrahydrofuran(20 ml) was stirred at room temperature for 8 hours. The reactionmixture was concentrated and the residue was partitioned between ethylacetate and water. The extract was dried over anhydrous sodium sulfateand concentrated under reduced pressure. The residue was chromatographedon a silica gel column using hexane : ethyl acetate=2:3 as the eluant toafford t-butyl N-{5-hydroxy-2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethylcarbonylamino]phenyl}-N-methylcarbamate (0.75 g).

[0830] A suspension of this carbamate (0.75 g) in 4N hydrogenchloride/dioxane (10 ml) was allowed to stand at room temperature for 19hours. The solvent of the reaction mixture was evaporated under reducedpressure. Ethyl acetate was added to the residue and the mixture wastreated with ultrasonic waves, filtered and then dried to afford thetitle compound (0.52 g, mp 217-220° C.).

[0831] Reference example 29

[0832] t-Butyl N-(5-benyloxy-2-nitrophenyl)-N-methylcarbamate

[0833] A mixture of sodium hydride (5.24 g, 55% dispersion in mineraloil), benzyl alcohol (13 g) and anhydrous N,N-dimethylformamide (150 ml)was stirred at room temperature for 30 minutes. To this mixture wasadded t-butyl N-(5-chloro-2-nitrophenyl) -N-methylcarbamate (8.7 g) atroom temperature and this mixture was stirred for 18 hours. The reactionmixture was concentrated and the residue was partitioned between ethylacetate and water. The extract was washed with saturated aqueous sodiumchloride solution, dried over anhydrous sodium sulfate and concentrated.The residue was chromatographed on a silica gel column using hexane :ethyl acetate=10:1 as the eluant to afford the title compound (29.2 g,yellow crystals, mp 108-110° C.).

[0834] Reference example 30

[0835] t-Butyl N-(2-amino-5-hydroxyphenyl)-N-methylcarbamate

[0836] A mixture of t-butylN-(5-benzyloxy-2-nitrophenyl)-N-methylcarbamate (15 g), palladium oncarbon (3 g, 10%), toluene (150 ml) and methanol (150 ml) was stirredunder a hydrogen atmosphere at room temperature for 12.5 hours. Thepalladium on carbon was filtered and the filtrate was concentrated toafford the title compound (12.3 g, brown oil, Rf=0.15 : thin layerchromatography on a silica gel plate using hexane : ethyl acetate=4 : 1as the eluant).

[0837] Reference example 31

[0838] Ethyl 3-(4-hydroxyphenyl)-2-mercapropropionate

[0839] A mixture of 5-(4-acetoxybenzyl)thiazolidine-2,4-dione (100 g),potassium hydroxide (150 g), distilled water (500 ml) and ethanol (500ml) was stirred at 75° C. for 2.5 hours and potassium hydroxide (250 g)was further added to the reaction mixture. This mixture was stirred at75° C. for 2 hours, allowed to stand overnight and then concentrated to300 ml. The mixture was poured into ice-water, adjusting to pH 3 withconcentrated hydrochloric acid and extracted with ethyl acetate. Theextract was washed with saturated aqueous sodium chloride solution,dried over anhydrous magnesium sulfate and concentrated. To a solutionof the residual oil in anhydrous ethanol (500 ml) was added 4N hydrogenchloride/dioxane (500 ml) at room temperature and the mixture wasallowed to stand for 2 days. The reaction mixture was concentrated andthe residue was purified by liquid chromatography on silica gel usinghexane : ethyl acetate=3:1 as the eluant to afford the title compound(50.1 g, pale yellow oil, Rf=0.87 : thin layer chromatography on asilica gel plate using hexane : ethyl acetate=1:1 as the eluant).

[0840] Reference example 32

[0841] Ethyl 3-(4-hydroxyphenyl)-2-methylthiopropionate

[0842] A mixture of Ethyl 3-(4-hydroxyphenyl)-2-mercaptopropionate (30g), methyl iodide (28.4 g), triethylamine (20.2 g) and tetrahydrofuran(150 ml) was stirred at room temperature for 7 hours. The reactionmixture was concentrated and the residue was partitioned between tolueneand water. The extract was washed with saturated aqueous sodium chloridesolution, dried over anhydrous magnesium sulfate and concentrated toafford the title compound (30.3 g, pale yellow oil, Rf=0.37 : thin layerchromatography on a silica gel plate using hexane : ethyl acetate=4:1 asthe eluant).

[0843] Reference example 33

[0844] Ethyl 3-(4-t-butoxycarbonylmethoxyphenyl)-2-methylthiopropionate

[0845] The title compound (24.3 g, pale yellow oil, Rf=0.46 : thin layerchromatography on a silica gel plate using hexane : acetate=7:1 as theeluant) was obtained by a similar procedure to that described inReference example 21 using ethyl3-(4-hydroxyphenyl)-2-methylthiopropionate (14 g), cesium carbonate(28.5 g), t-butyl bromoacetate (20 g) and acetonitrile (200 ml).

[0846] Reference example 34

[0847] Ethyl 3-(4-carboxymethoxyphenyl)-2-methylthiopropionate

[0848] The title compound (11.9 g, mp 77-78° C., milk white powder) wasobtained by a similar procedure to that described in Reference example 3using ethyl 3-(4-t-butoxycarbonylmethoxyphenyl) -2-methylthiopropionate(24 g) and 4N hydrogen chloride/dioxane (150 ml).

[0849] Reference example 35

[0850] t-ButylN-[2-[4-(2-methylthio-2-ethoxycarbonylethyl)phenoxyacetylamino]-5-hydroxyphenyl]-N-methylcarbamate

[0851] The title compound (11.1 g, Rf=0.14 : thin layer chromatographyon a silica gel plate using hexane : ethyl acetate=2:1 as the eluant)was obtained by a similar procedure to that described in Referenceexample 6 using t-butly N-(2-amino-5-hydroxyphenyl) -N-methylcarbamate(2.2 g), 3-(4-carboxymethoxyphenyl)-2-mehylthiopropionate (12.2 g),triethylamine (6.1 g), anhydrous tetrahydrofuran (250 ml) and diethylcyanophosphonate (9.79 g).

[0852] Reference example 36

[0853] 2-(N-t-butoxycarbonyl-N-methylamino)-4-methylthionitrobenzene

[0854] A mixture of4-chloro-2-(N-t-butoxycarbonyl-N-methylamino)nitrobenzene (57.3 g),sodium thiomethoxide (21.0 g) and anhydrous N,N-dimethylformamide (400ml) was stirred at room temperature for 23 hours. The reaction mixturewas partitioned between ethyl acetate and water. The extract was driedover anhydrous sodium sulfate and concentrated. The residue wasirradiated with ultarsonic waves in n-hexane. The insoluble product wascollected by filtration and washed with n-hexane to afford the titlecompound (55.9 g, mp 114-117° C.).

[0855] Reference example 37

[0856]2-Acetylthio-3-[4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]propionic acid

[0857] To a mixture of2-mercapto-3-[4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phyenyl]propionicacid hydrochloride (1.5 g), pyridine (0.87 g), tetrahydrofuran (30 ml)and N,N-dimethylformamide (30 ml) was added acetic anhydride (0.56 g).The mixture was stirred at room temperature for 5 hours and allowed tostand for 36 hours and then concentrated. The residual insolublematerial was collected by filtration and washed with ethyl acetate toafford the title compound (1.55 g, mp 209-214° C., pale yellow powder).

[0858] [EXPERIMENT] Hypoglycemic Activity:

[0859] Blood was collected from the tail veins of KK mice (4-5 monthsold) suffering from diabetes mellitus, and it was subjected to an assayof the blood sugar level. The mice were divided in groups (4 mice pergroup) as to have equal blood sugar levels on average in each group.Powdered mouse feed (F-1, Funabashi Farm) containing 0.01% of a testcompound was given the mice for 3 days. Those mice groups fed with thetest compound were referred to as “drug treated group”. Further, thosegroups fed with powdered feed free of the test compound were referred toas “control group”. Blood was collected from the tail veins of the mice3 days later and was subjected to a centrifuge, and the glucoseconcentration in the resultant plasma was assayed with a glucoseanalyzer (Glucolaoder, A&T Company). The average blood sugar loweringrate was calculated from the following formula:

[0860] Blood sugar lowering rate (%)= (Average blood sugar level incontrol group−Average blood sugar level in drug treated group)×100/Bloodsugar level in control group TABLE 6 Blood sugar Test Compound loweringrate (%) Compound in Example 2 58.5  4 40.8  9 48.4 16 32.1 20 40.0

[0861] [Formulation examples] (1) Capsules Compound of Example 2 10 mgLactose 110 mg  Corn starch 58 mg Magnesium stearate  2 mg 180 mg 

[0862] Each ingredient powder as shown above was admixed well and passedthrough a sieve of 60 mesh (mesh standard: Tyler standard). Theresultant powder (180 mg) was used to fill a gelatin capsule (No. 3).(2) Tablets: Compound of Example 2 10 mg Lactose 85 mg Corn starch 34 mgFinely crystalline cellulose 20 mg Magnesium stearate  1 mg 150 mg 

[0863] Each ingredient powder as shown above was admixed well and thencharged to a tableting compression mold (150 mg). If needed, the tabletmay be coated with sugar or a film. (3) Granules: Compound of Example 2 10 mg Lactose 839 mg Corn starch 150 mg Hydroxypropyl cellulose  1 mg1000 mg 

[0864] Each ingredient powder as shown above was admixed well, moistenedwith purified water and charged to a basket type granulating machine forgranulation. The resultant granules were dried.

[0865] The compound having the general formula (I) to (IV) above,pharmacologically acceptable salts thereof, pharmacologically acceptableesters thereof, or pharmacologically acceptable amides thereof, showingexcellent insulin resistance improving activity, hypoglycemic activity,anti-inflammatory activity, immunoregulatory activity, aldose reductaseinhibiting activity, 5-liposygenase inhibiting activity, peroxidizedlipid production suppressing activity, PPAR activating activity,anti-osteoporosis activity, leukotrienes anatagonistic activity, adiposecell formation promoting activity, cancer cell proliferation suppressingactivity or calcium antagonism, are useful for treatment and prophylaxisof such diseases as diabetes mellitus, hyperlipemia, obesity, impairedglucose tolerance, hypertension, fatty liver, diabetic complications(e.g. retinopathy, nephropathy, neurosis, cataract, coronary arterydiseases, etc.), arteriosclerosis, gestational diabetes mellitus,polycystic ovary syndrome, cardiovascular diseases (e.g. ischemic heartdisease, etc.), cell injury lesion (e.g. cerebral injury induced bystroke, etc.) caused by atherosclerosis or ischemic heart disease, gout,inflammatory diseases (e.g. arthrostesis, pain, fervescence, rheumaticarthritis, inflammatory enteritis, acne, sunburn, psoriasis, eczema,allergic diseases, asthma, GI ulcer, cachexia, autoimmune disease,pancreatitis, etc.), cancer, osteoporosis, cataract, etc. Further theuse of (i) at least one selected from α-glucosidase inhibitors, aldosereductase inhibitors, biguanides, statin type compounds, squalenesynthesis inhibitors, fibrate type compounds, LDL dissimilationpromotors, angiotensin converting enzyme inhibitors, and RXR activatorstogether with (ii) at least one compound having the general formula (I)to (IV) above, pharmacologically acceptable salts thereof,pharmacologically acceptable esters thereof or pharmacologicallyacceptable amides thereof are also useful for treatment and/orprevention of said diseases, and particularly for the treatment and/orprevention of diabetes mellitus and diabetic complications.

1. An α-substituted carboxylic acid derivative having the generalformula (II):

wherein: R₁, R₂ and R₃ are the same or different, and each is a (i)hydrogen atom, (ii) C₁-C₆ alkyl group, (iii) C₆-C₁₀ aryl group(optionally having 1-5 substituents α₁ hereafter defined), (iv) C₇-C₁₆aralkyl group (optionally having 1-5 substituents α₁ hereafter definedon the aryl moiety thereof), (v) C₁-C₆ alkylsulfonyl group, (vi) C₁-C₆halogenoalkylsulfonyl group, (vii) C₆-C₁₀ arylsulfonyl group (optionallyhaving 1-5 substituents α₁ hereafter defined) or (viii) C₇-C₁₆aralkylsulfonyl group (optionally having 1-5 substituents α₁ hereafterdefined on the aryl moiety thereof); A is a nitrogen atom or a═CH-group; B is an oxygen atom or a sulfur atom; W₁ is a C₁-C₈ alkylenegroup; W₂ is a single bond or a C₁-C₈ alkylene group; X is a (i)hydrogen atom, (ii) C₁-C₆ alkylene group, (iii) C₁-C₆ halogenoalkylgroup, (iv) C₁-C₆ alkoxy group, (v) halogen atom, (vi) hydroxy group,(vii) cyano group, (viii) nitro group. (ix) C₃-C₁₀ cycloalkyl group, (x)C₆-C₁₀ aryl group (optionally having 1-5 substituents β hereafterdefined), (xi) C₇-C₁₆ aralkyl group (optionally having 1-5 substituentsβ hereafter defined on the aryl moiety thereof), (xii) C₁-C₇ aliphaticacyl group, (xiii) C₄-C₁₁ cycloalkylcarbonyl group, (xiv) C₇-C₁₁arylcarbonyl group (optionally having 1-5 substituents β hereafterdefined), (xv) C₈-C₁₇ aralkylcarbonyl group (optionally having 1-5substituents β hereafter defined on the aryl moiety thereof), (xvi)monocyclic type heteroaromatic ring-carbonyl group (optionally having1-5 substituents β hereafter defined), (xvii) carbamoyl group, (xviii)C₇-C₁₁ arylaminocarbonyl group (optionally having 1-5 substituents βhereafter defined on the aryl moiety thereof) or (xix) amino group(optionally having 1 to 2 substituents β defined hereafter); Y is anoxygen atom or an S(O)p group (wherein p is an integer from 0 to 2); Z₂is a saturated heterocyclic ring (optionally having 1-5 substituents α₁hereafter defined) or a C₆-C₁₀ aryl group (having 1-5 substituents α₂hereafter defined), said substituent α₁ is a (i) C₁-C₆ alkyl group, (ii)C₁-C₆ halogenoalkyl group, (iii) C₁-C₆ alkoxy group, (iv) halogen atom,(v) hydroxy group, (vi) cyano group, (vii) nitro group, (viii) C₃-C₁₀cycloalkyl group, (ix) C₆-C₁₀ aryl group (optionally having 1-5substituents β hereafter defined), (x) C₇-C₁₆ aralkyl group (optionallyhaving 1-5 substituents β hereafter defined on the aryl moiety thereof),(xi) C₁-C₇ aliphatic acyl group, (xii) C₄-C₁₁ cycloalkylcarbonyl group,(xiii) C₇-C₁₁ arylcarbonyl group (optionally having 1-5 substituents βhereafter defined), (xiv) C₈-C₁₇ aralkylcarbonyl group (optionallyhaving 1-5 substituents β hereafter defined on the aryl moiety thereof),(xv) monocyclic type heteroaromatic ring-carbonyl group (optionallyhaving 1-5 substituents β hereafter defined), (xvi) carbamoyl group,(xvii) C₇-C₁₁ arylaminocarbonyl group (optionally having 1-5substituents β hereafter defined on the aryl moiety thereof), (xviii)amino group (optionally having 1 to 2 substituents β hereafter defined)or (xix) carboxyl group; said substituent α₂ is a (i) C₃-C₁₀ cycloalkylgroup, (ii) C₆-C₁₀ aryl group (optionally having 1-5 substituents βhereafter defined), (iii) C₇-C₁₆ aralkyl group (optionally having 1-5substituents β hereafter defined on the aryl moiety thereof), (iv) C₁-C₇aliphatic acyl group, (v) C₄-C₁₁ cycloalkylcarbonyl group, (vi) C₇-C₁₁arylcarbonyl group (optionally having 1-5 substituents β hereafterdefined), (vii) C₈-C₁₇ aralkylcarbonyl group (optionally having 1-5substituents β hereafter defined on the aryl moiety thereof, (viii)monocyclic type heteroaromatic ring-carbonyl group (optionally having1-5 substituents β hereafter defined), or (ix) C₇-C₁₁ arylaminocarbonylgroup (optionally having 1-5 substituents β hereafter defined on thearyl moiety thereof); said substituent β is a (i) C₁-C₁₀ alkyl group,(ii) halogen atom, (iii) C₆-C₁₀ aryl group (optionally having 1-5substituents γ hereafter defined), (iv) C₇-C₁₆ aralkyl group (optionallyhaving 1-5 substituents γ hereafter defined on the aryl moiety thereof),(v) C₁-C₇ aliphatic acyl group, (vi) C₇-C₁₁ arylcarbonyl group(optionally having 1-5 substituents γ hereafter defined), (vii) C₈-C₁₇aralkylcarbonyl group (optionally having 1-5 substituents γ hereafterdefined on the aryl moiety thereof), (viii) C₄-C₁₁ cycloalkylcarbonylgroup, (ix) monocyclic type heteroaromatic ring-carbonyl group(optionally having 1-5 substituents γ hereafter defined), (x) carbamoylgroup or (xi) C₇-C₁₁ arylaminocarbonyl group (optionally having 1-5substituents γ hereafter defined on the aryl moiety thereof); and saidsubstituent γ is a C₁-C₆ alkyl group, a C₁-C₆ halogenoalkyl group, ahalogen atom or a hydroxy group; or a pharmacologically acceptable esterthereof, a pharmacologically acceptable amide thereof or apharmacologically acceptable salt thereof.
 2. An α-substitutedcarboxylic acid derivative according to claim 1, wherein Z₂ is atetrahydropyranyl group (optionally having 1-5 substituents α₁), or apharmacologically acceptable ester thereof, a pharmacologicallyacceptable amide thereof or a pharmacologically acceptable salt thereof.3. An α-substituted carboxylic acid derivative according to claim 1,wherein Z₂ is a phenyl group (having one substituent α₂), or apharmacologically acceptable ester thereof, a pharmacologicallyacceptable amide thereof or a pharmacologically acceptable salt thereof.4. An α-substituted carboxylic acid derivative according to any one ofclaims 1 to 3, wherein α₂ is a (i) C₆-C₁₀ cycloalkyl group, (ii) phenylgroup (optionally having 1-3 substituents β), (iii) phenylcarbonyl group(optionally having 1-3 substituents β) or (iv) monocyclic typeheteroaromatic ring-carbonyl group (optionally having 1-3 substituentsβ), or a pharmacologically acceptable ester thereof, a pharmacologicallyacceptable amide thereof or a pharmacologically acceptable salt thereof.5. An α-substituted carboxylic acid derivative according to any one ofclaims 1 to 3, wherein α₂ is a C₆-C₁₀ cycloalkyl group, or apharmacologically acceptable ester thereof, a pharmacologicallyacceptable amide thereof or a pharmacologically acceptable salt thereof.6. An α-substituted carboxylic acid derivative according to claim 1,wherein: R₁, R₂ and R₃ are the same or different, and each is a (i)hydrogen atom, (ii) C₁-C₄ alkyl group or (iii) benzyl group (optionallyhaving one substituent α₁ on the phenyl moiety thereof; A is a═CH-group; B is an oxygen atom; W₁ is a C₁-₂ alkylene group; W₂ is aC₁-₂ alkylene group; X is a hydrogen atom; Y is an oxygen atom or anS(O)p group (in which p is an integer of 0-2); Z₂ is a tetrahydropyranylgroup (optionally having 1-5 substituents α₁); and said substituent α₁is a hydroxy group or a carboxyl group; or a pharmacologicallyacceptable ester thereof, a pharmacologically acceptable amide thereofor a pharmacologically acceptable salt thereof.
 7. An α-substitutedcarboxylic acid derivative according to claim 1, wherein: R₁, R₂ and R₃are the same or different, and each is a (i) hydrogen atom, (ii) C₁-C₄alkyl group or (iii) benzyl group (optionally having one substituent α₁on the phenyl moiety thereof); A is a ═CH-group; B is an oxygen atom; W₁is a C₁-C₂ alkylene group; W₂ is a C₁-C₂ alkylene group; X is a hydrogenatom; Y is an oxygen atom or an S(O)p group (in which p is an integer of0-2); Z₂ is a phenyl group having one substituent α₂; said substituentα₁ is a halogen atom or an adamantyl group, and said substituent α₂ isan adamantyl group; or a pharmacologically acceptable ester thereof, apharmacologically acceptable amide thereof or a pharmacologicallyacceptable salt thereof.
 8. An α-substituted carboxylic acid derivativehaving the general formula (III):

wherein: R₁, R₂ and R₃ are the same or different, and each is a (i)hydrogen atom, (ii) C₁-C₆ alkyl group, (iii) C₆-C₁₀ aryl group(optionally having 1-5 substituents α₁ hereafter defined), (iv) C₇-C₁₆aralkyl group (optionally having 1-5 substituents α₁ hereafter definedon the aryl moiety thereof), (v) C₁-C₆ alkylsulfonyl group, (vi) C₁-C₆halogenoalkylsulfonyl group, (vii) C₆-C₁₀ arylsulfonyl group (optionallyhaving 1-5 substituents α₁ hereafter defined) or (viii) C₇-C₁₆aralkylsulfonyl group (optionally having 1-5 substituents α₁ hereafterdefined on the aryl moiety thereof); A is a nitrogen atom or a═CH-group; B is an oxygen atom or a sulfur atom; W₁ is a C₁-C₈ alkylenegroup; W₂ is a single bond or a C₁-C₈ alkylene group; X is a (i)hydrogen atom, (ii) C₁-C₆ alkyl group, (iii) C₁-C₆ halogenoalkyl group,(iv) C₁-C₆ alkoxy group, (v) halogen atom, (vi) hydroxy group, (vii)cyano group, (viii) nitro group, (ix) C₃-C₁₀ cycloalkyl group, (x)C₆-C₁₀ aryl group (optionally having 1-5 substituents β hereafterdefined), (xi) C₇-C₁₆ aralkyl group (optionally having 1-5 substituentsβ hereafter defined on the aryl moiety thereof), (xii) C₁-C₇ aliphaticacyl group (xiii) C₄-C₁₁ cycloalkylcarbonyl group, (xiv) C₇-C₁₁arylcarbonyl group (optionally having 1-5 substituents β hereafterdefined), (xv) C₈-C₁₇ aralkylcarbonyl group (optionally having 1-5substituent β hereafter defined on the aryl moiety thereof), (xvi)monocyclic type heteroaromatic ring-carbonyl group (optionally having1-5 substituents β hereafter defined), (xvii) carbamoyl group, (xviii)C₇-C₁₁ arylaminocarbonyl group (optionally having 1-5 substituents βhereafter defined on the aryl moiety thereof) or (xix) amino group(optionally having 1 to 2 substituents β defined hereafter); Y is anoxygen atom or an S(O)p group (wherein p is an integer from 0 to 2); Z₃is a (i) C₁-C₆ alkyl group, (ii) C₆-C₁₀ aryl group (optionallycontaining 1-5 substituents α₁ hereafter defined), (iii) C₇-C₁₆ aralkylgroup (optionally containing 1-5 substituents α₁ hereafter defined onthe aryl moiety thereof), (iv) C₃-C₁₀ cycloalkyl group or (v) saturatedheterocyclic ring group (optionally containing 1-5 substituents α₁hereafter defined); said substituent α₁ is a (i) C₁-C₆ alkyl group, (ii)C₁-C₆ halogenoalkyl group, (iii) C₁-C₆ alkoxy group, (iv) halogen atom,(v) hydroxy group, (vi) cyano group, (vii) nitro group, (viii) C₃-C₁₀cycloalkyl group, (ix) C₆-C₁₀ aryl group (optionally having 1-5substituents β hereafter defined), (x) C₇-C₁₆ aralkyl group (optionallyhaving 1-5 substituents β hereafter defined on the aryl moiety thereof),(xi) C₁-C₇ aliphatic acyl group, (xii) C₄-C₁₁ cycloalkylcarbonyl group,(xiii) C₇-C₁₁ arylcarbonyl group optionally having 1-5 substituents βhereafter defined), (xiv) C₈-C₁₇ aralkylcarbonyl group (optionallyhaving 1-5 substituents β hereafter defined on the aryl moiety thereof),(xv) monocyclic type heteroaromatic ring-carbonyl group (optionallyhaving 1-5 substituents β hereafter defined), (xvi) carbamoyl group,(xvii) C₇-C₁₁ arylaminocarbonyl group (optionally having 1-5substituents β hereafter defined on the aryl moiety thereof), (xviii)amino group (optionally having 1 to 2 substituents β defined hereafter)or (xix) carboxyl group; said substituent β is a (i) C₁-C₁₀ alkyl group,(ii) halogen atom, (iii) C₆-C₁₀ aryl group (optionally having 1-5substituents γ hereafter defined), (iv) C₇-C₁₆ aralkyl group (optionallyhaving 1-5 substituents γ hereafter defined on the aryl moiety thereof),(v) C₁-C₇ aliphatic acyl group, (vi) C₇-C₁₁ arylcarbonyl group(optionally having 1-5 substituents γ hereafter defined), (vii) C₈-C₁₇aralkylcarbonyl group (optionally having 1-5 substituents γ hereafterdefined on the aryl moiety thereof), (viii) C₄-C₁₁ cycloalkylcarbonylgroup, (ix) monocyclic type heteroaromatic ring-carbonyl group(optionally having 1-5 substituents γ hereafter defined), (x) carbamoylgroup or (xi) C₇-C₁₁ arylaminocarbonyl group (optionally having 1-5substituents γ hereafter defined on the aryl moiety thereof; and saidsubstituent γ is a C₁-C₆ alkyl group, a C₁-C₆ halogenoalkyl group, ahalogen atom or a hydroxy group; or a pharmacologically acceptable esterthereof, a pharmacologically acceptable amide thereof or apharmacologically acceptable salt thereof.
 9. An α-substitutedcarboxylic acid derivative according to claim 8, wherein Z₃ is a (i)C₁-C₄ alkyl group, (ii) C₆-C₁₀ aryl group (optionally having 1-3substituents α₁) or (iii) C₃-C₁₀ cycloalkyl group), or apharmacologically acceptable ester thereof a pharmacologicallyacceptable amide thereof or a pharmacologically acceptable salt thereof.10. An α-substituted carboxylic acid derivative according to claim 8,wherein Z₃ is a phenyl group (optionally having 1-3 substituents α₁), ora pharmacologically acceptable ester thereof, a pharmacologicallyacceptable amide thereof or a pharmacologically acceptable salt thereof.11. An α-substituted carboxylic acid derivative according to claim 8,wherein: R₁, R₂ or R₃ are the same or different, and each is a (i)hydrogen atom, (ii) C₁-C₄ alkyl group or (iii) benzyl group (optionallyhaving one substituent α₁ on the phenyl moiety thereof); A is a═CH-group; B is an oxygen atom; W₁ is a C₁-C₂ alkylene group; W₂ is aC₁-C₂ alkylene group; X is a hydrogen atom; Y is an oxygen atom or anS(O)p group (in which p is an integer of 0-2); Z₃ is a (i) C₁-C₄ alkylgroup, (ii) C₆-C₁₀ aryl group (optionally having 1-3 substituents α₁) or(iii) C₃-C₁₀ cycloalkyl group; and said substituent α₁ is a (i) C₁-C₄alkyl group, (ii) halogen atom, (iii) hydroxy group or (iv) adamantylgroup; or a pharmacologically acceptable ester thereof, apharmacologically acceptable amide thereof or a pharmacologicallyacceptable salt thereof.
 12. An α-substituted carboxylic acid derivativeaccording to claim 8, wherein: R₁ is a C₁-C₂ alkyl group; R₂ is ahydrogen atom; R₃ is a C₁-C₄ alkyl group or a phenyl-C₁-C₄ alkyl group(optionally having one substituent α₁ on the phenyl moiety thereof); Ais a ═CH-group; B is an oxygen atom; W₁ is a methylene group; W₂ is amethylene group; X is a hydrogen atom; Y is an oxygen atom or an S(O)pgroup (in which p is an integer of 0-2); Z₃ is a phenyl group(optionally having 1-3 substituents α₁); and said substituent α₁ is aC₁-C₄ alkyl group or a hydroxy group; or a pharmacologically acceptableester thereof, a pharmacologically acceptable amide thereof or apharmacologically acceptable salt thereof.
 13. An α-substitutedcarboxylic acid derivative having the general formula (IV):

wherein: R₁, R₂ and R₃ are the same or different, and each is a (i)hydrogen atom, (ii) C₁-C₆ alkyl group, (iii) C₆-C₁₀ aryl group(optionally having 1-5 substituents α₁ hereafter defined), (iv) C₇-C₁₆aralkyl group (optionally having 1-5 substituents α₁ hereafter definedon the aryl moiety thereof), (v) C₁-C₆ alkylsulfonyl group, (vi) C₁-C₆halogenoalkylsulfonyl group, (vii) C₆-C₁₀ arylsulfonyl group (optionallyhaving 1-5 substituents α₁ hereafter defined) or (viii) C₇-C₁₆aralkylsulfonyl group (optionally having 1-5 substituents α₁ hereafterdefined on the aryl moiety thereof); R₄ is a (i) C₁-C₆ alkyl group, (ii)C₆-C₁₀ aryl group (optionally having 1-5 substituents α₁ hereafterdefined) or (iii) C₇-C₁₆ aralkyl group (optionally having 1-5substituents α₁ hereafter defined on the aryl moiety thereof); A is anitrogen atom or a ═CH-group; B is an oxygen atom or a sulfur atom; W₁is a C₁-C₈ alkylene group; W₂ is a single bond or a C₁-C₈ alkylenegroup; X is a (i) hydrogen atom, (ii) C₁-C₆ alkyl group, (iii) C₁-C₆halogenoalkyl group, (iv) C₁-C₆ alkoxy group, (v) halogen atom, (vi)hydroxy group, (vii) cyano group, (viii) nitro group, (ix) C₃-C₁₀cycloalkyl group, (x) C₆-C₁₀ aryl group (optionally having 1-5substituents β hereafter defined), (xi) C₇-C₁₆ aralkyl group (optionallyhaving 1-5 substituents β hereafter defined on the aryl moiety thereof),(xii) C₁-C₇ aliphatic acyl group, (xiii) C₄-C₁₁ cycloalkylcarbonylgroup, (xiv) C₇-C₁₁ arylcarbonyl group (optionally having 1-5substituents β hereafter defined), (xv) C₈-C₁₇ aralkylcarbonyl group(optionally having 1-5 substituents β hereafter defined on the arylmoiety thereof), (xvi) monocyclic type heteroaromatic ring-carbonylgroup (optionally having 1-5 substituents β hereafter defined), (xvii)carbamoyl group, (xviii) C₇-C₁₁ arylaminocarbonyl group (optionallyhaving 1-5 substituents β hereafter defined on the aryl moiety thereof)or (xix) amino group (optionally having 1 to 2 substituents β definedhereafter); Y is an oxygen atom or an S(O)p group (wherein p is aninteger from 0 to 2); Z₄ is a (i) C₁-C₆ alkoxy group, (ii) C₁-C₆alkylthio group, (iii) halogen atom, (iv) C₆-C₁₀ aryl group (optionallyhaving 1-5 substituents α₁ hereafter defined), (v) C₇-C₁₆ aralkyl group(optionally having 1-5 substituents α₁ hereafter defined on the arylmoiety thereof), (vi) C₆-C₁₀ aryloxy group (optionally having 1-5substituents α₁ hereafter defined), (vii) C₇-C₁₆ aralkyloxy group(optionally having 1-5 substituents α₁ hereafter defined on the arylmoiety thereof), (viii) C₃-C₁₀ cycloalkyloxy group, (ix) C₃-C₁₀cycloalkylthio group, (x) saturated heterocyclic ring-oxy group(optionally having 1-5 substituents α₁ hereafter defined), (xi)monocyclic type heteroaromatic ring-oxy group (optionally having 1-5substituents α₁ hereafter defined), (xii) C₆-C₁₀ arylthio group(optionally having 1-5 substituents α₁ hereafter defined), (xiii) C₇-C₁₆aralkylthio group (optionally having 1-5 substituents α₁ hereafterdefined on the aryl moiety thereof, (xiv) saturated heterocyclicring-thio group (optionally having 1-5 substituents α₁ hereafterdefined), (xv) monocyclic type heteroaromatic ring-thio group(optionally having 1-5 substituents α₁ hereafter defined), (xvi) aminogroup (optionally having 1-2 substituents α₁ hereafter defined) or(xvii) hydroxy group; said substituent α₁ is a (i) C₁-C₆ alkyl group,(ii) C₁-C₆ halogenoalkyl group, (iii) C₁-C₆ alkoxy group, (iv) halogenatom, (v) hydroxy group, (vi) cyano group, (vii) nitro group, (viii)C₃-C₁₀ cycloalkyl group, (ix) C₆-C₁₀ aryl group (optionally having 1-5substituents β hereafter defined), (x) C₇-C₁₆ aralkyl group (optionallyhaving 1-5 substituents β hereafter defined on the aryl moiety thereof),(xi) C₁-C₇ aliphatic acyl group, (xii) C₄-C₁₁ cycloalkylcarbonyl group,(xiii) C₇-C₁₁ arylcarbonyl group (optionally having 1-5 substituents βhereafter defined), (xiv) C₈-C₁₇ aralkylcarbonyl group (optionallyhaving 1-5 substituents β hereafter defined on the aryl moiety thereof),(xv) monocyclic type heteroaromatic ring-carbonyl group (optionallyhaving 1-5 substituents β hereafter defined), (xvi) carbamoyl group,(xvii) C₇-C₁₁ arylaminocarbonyl group (optionally having 1-5substituents β hereafter defined on the aryl moiety thereof), (xviii)amino group (optionally having 1 to 2 substituents β defined hereafter)or (xix) carboxyl group; said substituent β is a (i) C₁-C₁₀ alkyl group,(ii) halogen atom, (iii) C₆-C₁₀ aryl group (optionally having 1-5substituents γ hereafter defined), (iv) C₇-C₁₆ aralkyl group (optionallyhaving 1-5 substituents γ hereafter defined on the aryl moiety thereof),(v) C₁-C₇ aliphatic acyl group, (vi) C₇-C₁₁ arylcarbonyl group(optionally having 1-5 substituents γ hereafter defined), (vii) C₈-C₁₇aralkylcarbonyl group (optionally having 1-5 substituents γ hereafterdefined on the aryl moiety thereof), (viii) C₄-C₁₁ cycloalkylcarbonylgroup, (ix) monocyclic type heteroaromatic ring-carbonyl groupoptionally having 1-5 substituents γ hereafter defined), (x) carbamoylgroup or (xi) C₇-C₁₁ arylaminocarbonyl group (optionally having 1-5substituents γ hereafter defined on the aryl moiety thereof); and saidsubstituent γ is a C₁-C₆ alkyl group, a C₁-C₆ halogenoalkyl group, ahalogen atom or a hydroxy group; or a pharmacologically acceptable esterthereof a pharmacologically acceptable amide thereof or apharmacologically acceptable salt thereof.
 14. An α-substitutedcarboxylic acid derivative according to claim 13, wherein R₄ is a C₁-C₄alkyl group or a phenyl group (optionally having 1-3 substituents α₁),or a pharmacologically acceptable ester thereof, a pharmacologicallyacceptable amide thereof or a pharmacologically acceptable salt thereof.15. An α-substituted carboxylic acid derivative according to claim 13,wherein R₄ is a phenyl group (optionally having one substituent α₁)), ora pharmacologically acceptable ester thereof, a pharmacologicallyacceptable amide thereof or a pharmacologically acceptable salt thereof.16. An α-substituted carboxylic acid derivative according to any one ofclaims 13 to 15, wherein Z₄ is a (i) C₁-C₄ alkoxy group, (ii) C₁-C₂alkylthio group, (iii) phenoxy group (optionally having 1-3 substituentsα₁) or (iv) phenylthio group (optionally having 1-3 substituents α₁), ora pharmacologically acceptable ester thereof, a pharmacologicallyacceptable amide thereof or a pharmacologically acceptable salt thereof.17. An α-substituted carboxylic acid derivative according to any one ofclaims 13 to 15, wherein Z₄ is a C₁-C₂ alkoxy group, or apharmacologically acceptable ester thereof, a pharmacologicallyacceptable amide thereof or a pharmacologically acceptable salt thereof.18. An α-substituted carboxylic acid derivative according to any one ofclaims 13 to 15, wherein Z₄ is a phenoxy group (optionally having 1-3substituents α₁), or a pharmacologically acceptable ester thereof, apharmacologically acceptable amide thereof or a pharmacologicallyacceptable salt thereof.
 19. An α-substituted carboxylic acid derivativeaccording to claim 13, wherein: R₁ is a C₁-C₂ alkyl group; R₂ is ahydrogen atom; R₃ is a hydrogen atom; R₄ is a phenyl group (optionallyhaving one substituent α₁); A is a ═CH-group; B is an oxygen atom; W isa methylene group; W₂ is a methylene group; X is a hydrogen atom; Z₄ isa C₁-C₂ alkoxy group; and said substituent α₁ is a benzoyl group; or apharmacologically acceptable ester thereof, a pharmacologicallyacceptable amide thereof or a pharmacologically acceptable salt thereof.20. An α-substituted carboxylic acid derivative according to claim 13,wherein: R is a C₁-C₂ alkyl group; R₂ is a hydrogen atom; R is ahydrogen atom; R is a phenyl group (optionally having one substituentα₁); A is a ═CH-group; B is an oxygen atom; W is a methylene group W₂ isa methylene group; X is a hydrogen atom; Z₄ is a phenoxy group(optionally having 1-3 substituents α₁); said substituent α₁ is a C₁-C₄alkyl group, a benzoyl group or an amino group (optionally having onesubstituent β); said substituent β is a phenylaminocarbonyl group(optionally having one substituent γ on the phenyl moiety thereof); andsaid substituent γ is a trifluoromethyl group; or a pharmacologicallyacceptable ester thereof, a pharmacologically acceptable amide thereofor a pharmacologically acceptable salt thereof.
 21. An α-substitutedcarboxylic acid derivative selected from the group consisting of:3-[4-[6-(4-adamantan-1-ylphenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]phenyl]-2-(4-fluorobenzyloxy)propionicacid,3-[4-[6-(3,5-di-t-butyl-4-hydroxyphenylthio)-1-methyl-1H-benzimidazol-2-ylmethoxy]phenyl]-2-4-fluorobenzyloxy)propionicacid,4-[6-3,5-di-t-butyl-4-hydroxyphenylthio)-1-methyl-1H-benzimidazol-2-ylmethoxy]phenyllacticacid,4-[6-(4-hydroxy-2,3,5-trimethylphenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]phenyllacticacid, 4-(1-methyl-6-methoxy-1H-benzimidazol-2-ylmethoxy)phenylaceticacid,2-ethoxy-3-[4-(1-methyl-6-methoxy-1H-benzimidazol-2-ylmethoxy)phenyl]propionicacid,N-(2-benzoylphenyl)-4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenylalanine,4-[6-(4amino-3,5-dimethylphenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]-N-(2-benzoylphenyl)phenylalanine,4-[6-[4-(4-trifluoromethylphenylureido)-3,5-dimethylphenoxy]-1-methyl-1H-benzimidazol-2-ylmethoxy]-N-(2-benzoylphenyl)phenylalanine,3-[4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]-2-mercaptopropionicacid,3-[4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylthiopropionicacid,3-[4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylsulfenylpropionic3-[4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylsulfonylpropionicacid,3-[4-(6-hydroxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylthiopropionicacid, 3-[4-[6-(β-D-glucopyranosyloxyuronicacid)-1-methyl-1H-benzimidazol-2-ylmethoxy]phenyl]-2-methylthiopropionicacid,3-[4-(1-methyl-6-methylthio-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylthiopropionicacid, and3-[4-(1-methyl-6-methylthio-1H-benzimidazol-2-ylmethoxy)phenyl]-2-mercaptopropionicacid, or a pharmacologically acceptable ester thereof, apharmacologically acceptable amide thereof or a pharmacologicallyacceptable salt thereof.
 22. An α-substituted carboxylic acid derivativeor a pharmacologically acceptable ester thereof, a pharmacologicallyacceptable amide thereof or a pharmacologically acceptable salt thereofaccording to claim 21 selected from the group consisting of:3-[4-[6-(4-adamantan-1-ylphenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]phenyl]-2-(4-fluorobenzyloxy)propionicacid,3-[4-[6-(3,5-di-t-butyl-4-hydroxyphenylthio)-1-methyl-1H-benzimidazol-2-ylmethoxy]phenyl]-2-(4-fluorobenzyloxy)propionicacid,2-ethoxy-3-[4-(1-methyl-6-methoxy-1H-benzimidazol-2-ylmethoxy)phenyl]propionicacid,N-(2-benzoylphenyl)-4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenylalanine,4-[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]-N-(2-benzoylphenyl)phenylalanine,3-[4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylsulfenylpropionicacid, and3-[4-(1-methyl-6-methylthio-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylthiopropionicacid.
 23. An α-substituted carboxylic acid derivative according to claim22 which is3-[4-[6-(4adamantan-1-ylphenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]phenyl]-2(4-fluorobenzyloxy)propionicacid.
 24. An α-substituted carboxylic acid derivative according to claim22 which is3-[4-[6-(3,5-di-t-butyl-4-hydroxyphenylthio)-1-methyl-1H-benzimidazol-2-ylmethoxy]phenyl]-2-4-fluorobenzyloxy)propionicacid.
 25. An α-substituted carboxylic acid derivative according to claim22 which is2-ethoxy-3-[4-1-methyl-6-methoxy-1H-benzimidazol-2-ylmethoxy)phenyl]propionicacid.
 26. An α-substituted carboxylic acid derivative according to claim22 which isN-(2-benzoylphenyl)-4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenylalanine.27. An α-substituted carboxylic acid derivative according to claim 22which is4-[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]-N-(2-benzoylphenyl)phenylalanine.28. An α-substituted carboxylic acid derivative according to claim 22which is3-[4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylsulfenylpropionicacid.
 29. An α-substituted carboxylic acid derivative according to claim22 which is3-[4-(1-methyl-6-methylthio-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylthiopropionicacid.
 30. A pharmaceutical composition comprising an effective amount ofa pharmacologically active compound together with a carrier therefor,wherein said pharmacologically active compound is a compound accordingto any one of claims 1-3, 6-15 and 19-22 or a pharmacologicallyacceptable ester thereof, a pharmacologically acceptable amide thereofor a pharmacologically acceptable salt thereof.
 31. A pharmaceuticalcomposition comprising an effective amount of a pharmacologically activecompound together with a carrier therefor, wherein saidpharmacologically active compound is a compound according to claim 4 ora pharmacologically acceptable ester thereof, a pharmacologicallyacceptable amide thereof or a pharmacologically acceptable salt thereof.32. A pharmaceutical composition comprising an effective amount of apharmacologically active compound together with a carrier therefor,wherein said pharmacologically active compound is a compound accordingto claim 16 or a pharmacologically acceptable ester thereof, apharmacologically acceptable amide thereof or a pharmacologicallyacceptable salt thereof.
 33. A pharmaceutical composition comprising aneffective amount of a pharmacologically active compound together with acarrier therefor, wherein said pharmacologically active compound is acompound according to any one of claims 23 to
 29. 34. A method oftreating a human in need of treatment with an active agent selected fromthe group consisting of insulin resistance improving agents,hypoglycemia agents, immunoregulatory agents, aldose reductaseinhibitors, 5-lipoxygenase inhibitors, peroxidized lipid productionsuppressors, PPAR activators, leukotriene antagonists, adipose cellformation promoters and calcium antagonists comprising administering aneffective amount of said active agent to said human, wherein said activeagent is an α-substituted carboxylic acid derivative or apharmacologically acceptable ester thereof, a pharmacologicallyacceptable amide thereof or a pharmacologically acceptable salt thereofaccording to any one of claims 1-3, 6-5 and 19-29.
 35. A method oftreating a human in need of treatment with an active agent selected fromthe group consisting of insulin resistance improving agents,hypoglycemic agents, immunoregulatory agents, aldose reductaseinhibitors, 5-lipoxygenase inhibitors, peroxidized lipid productionsuppressors, PPAR activators, leukotriene antagonists, adipose cellformation promoters and calcium antagonists comprising administering aneffective amount of said active agent to said human, wherein said activeagent is an α-substituted carboxylic acid derivative or apharmacologically acceptable ester thereof, a pharmacologicallyacceptable amide thereof or a pharmacologically acceptable salt thereofaccording to claim
 5. 36. A method of treating a human in need oftreatment with an active agent selected from the group consisting ofinsulin resistance improving agents, hypoglycemic agents,immunoregulatory agents, aldose reductase inhibitors, 5-lipoxygenaseinhibitors, peroxidized lipid production suppressors, PPAR activators,leukotriene antagonists, adipose cell formation promotors and calciumantagonists comprising administering an effective amount of said activeagent to said human, wherein said active agent is an α-substitutedcarboxylic acid derivative or a pharmacologically acceptable esterthereof, a pharmacologically acceptable amide thereof or apharmacologically acceptable salt thereof according to claim
 17. 37. Amethod of treating a human in need thereof according to claim 34 whereinsaid active agent is a hypoglycemic agent.
 38. A method of treatment orprophylaxis of a disease selected from the group consisting of diabetesmellitus, impaired glucose tolerance, gestational diabetes mellitus,neurosis cataract and coronary artery diseases comprising administeringto a human in need thereof, an effective amount of an active agent,wherein said active agent is an α-substituted carboxylic acid derivativeor a pharmacologically acceptable ester thereof, a pharmacologicallyacceptable amide thereof or a pharmacologically acceptable salt thereofaccording to any one of claims 1-3, 6-15 and 19-22.
 39. A method oftreatment or prophylaxis of a disease selected from the group consistingof diabetes mellitus, impaired glucose tolerance, gestational diabetesmellitus, neurosis, cataract and coronary artery diseases comprisingadministering to a human in need thereof, an effective amount of anactive agent, wherein said active agent is an α-substituted carboxylicacid derivative or a pharmacologically acceptable ester thereof, apharmacologically acceptable amide thereof or a pharmacologicallyacceptable salt thereof according to claim
 4. 40. A method of treatmentor prophylaxis of a disease selected from the group consisting ofdiabetes mellitus, impaired glucose tolerance, gestational diabetesmellitus, neurosis, cataract and coronary artery diseases comprisingadministering to a human in need thereof an effective amount of anactive agent, wherein said active agent is an α-substituted carboxylicacid derivative or a pharmacologically acceptable ester thereof, apharmacologically acceptable amide thereof or a pharmacologicallyacceptable salt thereof according to claim
 18. 41. A method of treatmentor prophylaxis of a disease selected from the group consisting ofdiabetes mellitus, impaired glucose tolerance, gestational diabetesmellitus, neurosis, cataract and coronary artery diseases comprisingadministering to a human in need thereof, an effective amount of anactive agent, wherein said active agent is an α-substituted carboxylicacid derivative or a pharmacologically acceptable ester thereof, apharmacologically acceptable amide thereof or a pharmacologicallyacceptable salt thereof according to any one of claims 23-29.
 42. Amethod according to claim 38 wherein said disease is diabetes mellitus.43. A method according to claim 39 wherein said disease is diabetesmellitus.
 44. A method according to claim 40 wherein said disease isdiabetes mellitus.
 45. A method according to claim 41 wherein saiddisease is diabetes mellitus.
 46. A method of treatment or prophylaxisof a disease selected from the group consisting of diabetes mellitus,impaired glucose tolerance, gestational diabetes mellitus, neurosis,cataract and coronary artery diseases comprising administering to ananimal in need thereof, an effective amount of an active agent, whereinsaid active agent is an α-substituted carboxylic acid derivative of thegeneral formula (I):

wherein: R₁, R₂ and R₃ are the same or different, and each is a (i)hydrogen atom, (ii) C₁-C₆ alkyl group, (iii) C₆-C₁₀ aryl group(optionally having 1-5 substituents α₁ hereafter defined), (iv) C₇-C₁₆aralkyl group (optionally having 1-5 substituents α₁ hereafter definedon the aryl moiety thereof, (v) C₁-C₆ alkylsulfonyl group, (vi) C₁-C₆halogenoalkylsulfonyl group, (vii) C₆-C₁₀ arylsulfonyl group (optionallyhaving 1-5 substituents α₁ hereafter defined) or (viii) C₇-C₁₆aralkylsulfonyl group (optionally having 1-5 substituents α₁ hereafterdefined on the aryl moiety thereof); A is a nitrogen atom or a═CH-group; B is an oxygen atom or a sulfur atom; W₁ is a C₁-C₈ alkylenegroup; W₂ is a single bond or a C₁-C₈ alkylene group; X is a (i)hydrogen atom, (ii) C₁-C₆ alkyl group, (iii) C₁-C₆ halogenoalkyl group,(iv) C₁-C₆ alkoxy group, (v) halogen atom, (vi) hydroxy group, (vii)cyano group, (viii) nitro group, (ix) C₃-C₁₀ cycloalkyl group, (x)C₆-C₁₀ aryl group (optionally having 1-5 substituents β hereafterdefined), (xi) C₇-C₁₆ aralkyl group (optionally having 1-5 substituentsβ hereafter defined on the aryl moiety thereof, (xii) C₁-C₇ aliphaticacyl group, (xiii) C₄-C₁₁ cycloalkylcarbonyl group, (xiv) C₇-C₁₁arylcarbonyl group (optionally having 1-5 substituents β hereafterdefined), (xv) C₈-C₁₇ aralkylcarbonyl group (optionally having 1-5substituents β hereafter defined on the aryl moiety thereof), (xvi)monocyclic type heteroaromatic ring-carbonyl group (optionally having1-5 substituents β hereafter defined), (xvii) carbamoyl group, (xviii)C₇-C₁₁ arylaminocarbonyl group (optionally having 1-5 substituents βhereafter defined on the aryl moiety thereof) or (xix) amino group(optionally having 1 to 2 substituents β defined hereafter); Y is anoxygen atom or an S(O)p group (wherein p is an integer from 0 to 2); Z₁is a (i) hydrogen atom, (ii) C₁-C₆ alkyl group, (iii) C₁-C₆ alkoxygroup, (iv) C₁-C₆ alkylthio group, (v) halogen atom, (vi) C₆-C₁₀ arylgroup (optionally having 1-5 substituents α₁ hereafter defined), (vii)C₇-C₁₆ aralkyl group (optionally having 1-5 substituents α₁ hereafterdefined on the aryl moiety thereof), (viii) C₆C-₁₀ aryloxy group(optionally having 1-5 substituents α₁ hereafter defined), (ix) C₇-C₆aralkyloxy group (optionally having 1-5 substituents α₁ hereafterdefined on the aryl moiety thereof), (x) C₃-C₁₀ cycloalkyloxy group,(xi) C₃-C₁₀ cycloalkylthio group, (xii) saturated heterocyclic ring-oxygroup (optionally having 1-5 substituents α₁ hereafter defined), (xiii)monocyclic type heteroaromatic ring-oxy group (optionally having 1-5substituents α₁ hereafter defined), (xiv) C₆-C₁₀ arylthio group(optionally having 1-5 substituents α₁ hereafter defined), (xv) C₇-C₁₆aralkylthio group (optionally having 1-5 substituents α₁ hereafterdefined on the aryl moiety thereof), (xvi) saturated heterocyclicring-thio group (optionally having 1-5 substituents α₁ hereafterdefined), (xvii) monocyclic type heteroaromatic ring-thio group(optionally having 1-5 substituents α₁ hereafter defined), (xviii) aminogroup (optionally having 1-2 substituents α₁ hereafter defined) or (xix)hydroxy group; said substituent α₁ is a (i) C₁-C₆ alkyl group, (ii)C₁-C₆ halogenoalkyl group, (iii) C₁-C₆ alkoxy group (iv) halogen atom,(v) hydroxy group, (vi) cyano group, (vii) nitro group, (viii) C₃-C₁₀cycloalkyl group, (ix) C₆-C₁₀ aryl group (optionally having 1-5substituents β hereafter defined), (x) C₇-C₁₆ aralkyl group (optionallyhaving 1-5 substituents β hereafter defined on the aryl moiety thereof),(xi) C₁-C₇ aliphatic acyl group, (xii) C₄-C₁₁ cycloalkylcarbonyl group,(xiii) C₇-C₁₁ arylcarbonyl group (optionally having 1-5 substituents βhereafter defined), (xiv) C₈-C₁₇ aralkylcarbonyl group (optionallyhaving 1-5 substituents β hereafter defined on the aryl moiety thereof),(xv) monocyclic type heteroaromatic ring-carbonyl group (optionallyhaving 1-5 substituents β hereafter defined), (xvi) carbamoyl group,(xvii) C₇-C ₁₁ arylaminocarbonyl group (optionally having 1-5substituents β hereafter defined on the aryl moiety thereof), (xviii)amino group (optionally having 1 to 2 substituents β defined hereafter)or (xix) carboxyl group; said substituent β is a (i) C₁-C₁₀ alkyl group,(ii) halogen atom, (iii) C₆-C₁₀ aryl group (optionally having 1-5substituents γ hereafter defined), (iv) C₇-C₁₆ aralkyl group (optionallyhaving 1-5 substituents γ hereafter defined on the aryl moiety thereof),(v) C₁-C₇ aliphatic acyl group, (vi) C₇-C₁₁ arylcarbonyl group(optionally having 1-5 substituents γ hereafter defined), (vii) C₈-C₁₇aralkylcarbonyl group (optionally having 1-5 substituents γ hereafterdefined on the aryl moiety thereof), (viii) C₄-C₁₁ cycloalkylcarbonylgroup, (ix) monocyclic type heteroaromatic ring-carbonyl group(optionally having 1-5 substituents γ hereafter defined), (x) carbamoylgroup or (xi) C₇-C₁₁ arylaminocarbonyl group (optionally having 1-5substituents γ hereafter defined on the aryl moiety thereof); and saidsubstituent γ is a C₁-C₆ alkyl group, a C₁-C₆ halogenoalkyl group, ahalogen atom or a hydroxy group; or a pharmacologically acceptable esterthereof, a pharmacologically acceptable amide thereof or apharmacologically acceptable salt thereof.
 47. A method according toclaim 46 wherein R₁, R₂ and R₃ are the same or different and each is a(i) hydrogen atom, (ii) C₁-C₄ alkyl group, (iii) phenyl group(optionally having one substituent α₁ ), (iv) phenyl-C₁-C₂ alkyl group(optionally having 1-3 substituents α₁ on the phenyl moiety thereof) or(v) C₁-C₂ alkylsulfonyl group.
 48. A method according to claim 46wherein R₁, R₂ and R₃ are the same or different, and each is a (i)hydrogen atom, (ii) C₁-C₄ alkyl group or (iii) benzyl group (optionallyhaving one substituent α₁ on the phenyl moiety thereof).
 49. A methodaccording to claim 46 wherein R₁ is a C₁-C₂ alkyl group, R₂ is ahydrogen atom and R₃ is a C₁-C₄ alkyl group or a phenyl-C₁-C₄ alkylgroup (optionally having one substituent α₁ on the phenyl moietythereof).
 50. A method according to claim 46 wherein R₁ is a C₁-C₂ alkylgroup, R₂ is a hydrogen atom and R₃ is a hydrogen atom.
 51. A methodaccording to claim 46 wherein A is a ═CH-group.
 52. A method accordingto claim 46 wherein B is an oxygen atom.
 53. A method according to claim46 wherein W₁ is a C₁-C₄ alkylene group.
 54. A method according to claim46 wherein W₁ is a C₁-C₂ alkylene group.
 55. A method according to claim46 wherein W₂ is a C₁-C₄ alkylene group.
 56. A method according to claim46 wherein W₂ is a methylene group.
 57. A method according to claim 46wherein X is a (i) hydrogen atom, (ii) C₁-C₂ alkyl group, (iii) halogenatom, (iv) hydroxy group, (v) C₁-C₂ aliphatic acyl group or (vi) aminogroup.
 58. A method according to claim 46 wherein X is a hydrogen atom.59. A method according to claim 46 wherein Z₁ is a (i) C₁-C₂ alkoxygroup, (ii) C₁-C₂ alkylthio group, (iii) halogen atom, (iv) phenoxygroup (optionally having 1-5 substituents α₁), (v) saturatedheterocyclic ring-oxy group (optionally having 1-5 substituents α₁),(vi) phenylthio group (optionally having 1-5 substituents α₁), (vii)saturated heterocyclic ring-thio group (optionally having 1-5substituents α₁), (viii) amino group or (ix) hydroxy group.
 60. A methodaccording to claim 46 wherein Z₁ is a (i) C₁-C₂ alkoxy group, (ii) C₁-C₂alkylthio group, (iii) phenoxy group (optionally having 1-5 substituentsα₁), (iv) saturated heterocyclic ring-oxy group (optionally having 1-5substituents α₁), (v) phenylthio group (optionally having 1-5substituents α₁) or (vi) hydroxy group.
 61. A method according to claim46 wherein the substituent α₁is a (i) C₁-C₄ alkyl group, (ii) C₁-C₂halogenoalkyl group, (iii) C₁-C₂ alkoxy group, (iv) halogen atom, (v)hydroxy group, (vi) cyano group, (vii) nitro group, (viii) adamantylgroup, (ix) benzoyl group (optionally having one substituent β), (x)amino group (optionally having one substituent β) or (xi) carboxylgroup.
 62. A method according to claim 46 wherein the substituent α₁ isa (i) C₁-C₄ alkyl group, (ii) halogen atom, (iii) hydroxy group, (iv)adamantyl group, (v) benzoyl group, (vi) amino group (optionally havingone substituent β) or (vii) carboxyl group.
 63. A method according toclaim 46 wherein the substituent α₁ is C₁-C₄ alkyl group or hydroxygroup.
 64. A method according to claim 46 wherein the substituent α₁ isa halogen atom or an adamantyl group.
 65. A method according to claim 46wherein the substituent α₁ is a C₁-C₄ alkyl group, a benzoyl group or anamino group (optionally having one substituent β).
 66. A methodaccording to claim 46 wherein the substituent β is a (i) C₁-C₄ alkylgroup, (ii) halogen atom or (iii) phenylaminocarbonyl group (optionallyhaving 1-3 substituents γ on the phenyl moiety thereof).
 67. A methodaccording to claim 46 wherein the substituent β is a phenylaminocarbonylgroup (optionally having one substituent γ on the phenyl moiety thereof.68. A method according to claim 46 wherein the substituent γ is atrifluoromethyl group or a halogen atom.
 69. A method according to claim46 wherein the substituent γ is a trifluoromethyl group.
 70. A methodaccording to claim 46 wherein: R₁, R₂, and R₃ are the same or different,and each is a (i) hydrogen atom, (ii) C₁-C₄ alkyl group, (iii) phenylgroup (optionally having one substituent α₁), (iv) phenyl-C₁-C₂ alkylgroup (optionally having 1-3 substituents α₁ on the phenyl moietythereof) or (v) C₁-C₂ alkylsulfonyl group; A is a ═CH-group; B is anoxygen atom; W₁ is a C₁-C₂ alkylene group; W₂ is a C₁-C₂ alkylene group;X is a (i) hydrogen atom, (ii) C₁-C₂ alkyl group, (iii) halogen atom,(iv) hydroxy group, (v) C₁-C₂ aliphatic acyl group or (vi) amino group;Y is an oxygen atom or an S(O)p group (in which p is an integer of 0-2);Z₁ is a (i) C₁-C₂ alkoxy group, (ii) C₁-C₂ alkylthio group, (iii)halogen atom, (iv) phenoxy group (optionally having 1-5 substituentsα₁), (v) saturated heterocyclic ring-oxy group (optionally having 1-5substituents α₁), (vi) phenylthio group (optionally having 1-5substituents α₁), (vii) saturated heterocyclic ring-thio group(optionally having 1-5 substituents α₁), (viii) amino group or (ix)hydroxy group; said substituent α₁ is a (i) C₁-C₄ alkyl group (ii) C₁-C₂halogenoalkyl group, (iii) C₁-C₂ alkoxy group, (iv) halogen atom, (v)hydroxy group, (vi) cyano group, (vii) nitro group, (viii) adamantylgroup, (ix) benzoyl group (optionally having one substituent β), (x)amino group (optionally having one substituent β), or (xi) carboxylgroup; said substituent β is a (i) C₁-C₄ alkyl group, (ii) halogen atomor (iii) phenylaminocarbonyl group (optionally having 1-3 substituents γon the phenyl moiety thereof); and said substituent γ is atrifluoromethyl group or a halogen atom.
 71. A method according to claim46 wherein: R₁, R₂ and R₃ are the same or different, and each is a (i)hydrogen atom, (ii) C₁-C₄ alkyl group or (iii) benzyl group (optionallyhaving one substituent α₁ on the phenyl moiety thereof); A is a═CH-group; B is an oxygen atom; W₁ is a C₁-C₂ alkylene group; W₂ is amethylene group; X is a hydrogen atom; Y is an oxygen atom or an S(O)pgroup (in which p is an integer from 0-2); Z₁ is a (i) C₁-C₂ alkoxygroup, (ii) C₁-C₂ alkylthio group, (iii) phenoxy group (optionallyhaving 1-5 substituents α₁), (iv) saturated heterocyclic ring-oxy group(optionally having 1-5 substituents α₁), (v) phenylthio group(optionally having 1-5 substituents α₁) or (vi) hydroxy group; saidsubstituent α₁ is a (i) C₁-C₄ alkyl group (ii) halogen atom, (iii)hydroxy group, (iv) adamantyl group, (v) benzoyl group (vi) amino group(optionally having one substituent β) or (vii) carboxyl group; saidsubstituent β is a phenylaminocarbonyl group (optionally having onesubstituent γ on the phenyl moiety thereof); and said substituent γ is atrifluoromethyl group.
 72. A method according to any one of claims 46-71wherein said disease is diabetes mellitus.
 73. A method of treating ananimal in need of treatment with an active agent selected from the groupconsisting of insulin resistance improving agents, hypoglycemic agents,immunoregulatory agents, aldose reductase inhibitors, 5-lipoxygenaseinhibitors, peroxidized lipid production suppressors, PPAR activators,leukotriene antagonists, adipose cell formation promoters and calciumantagonists comprising administering an effective amount of said activeagent to said animal, wherein said active agent is an α-substitutedcarboxylic acid derivative of the general formula (I):

wherein: R₁, R₂ and R₃ are the same or different, and each is a (i)hydrogen atom, (ii) C₁-C₆ alkyl group. (iii) C₆-C₁₀ aryl group(optionally having 1-5 substituents α₁ hereafter defined), (iv) C₇-C₁₆aralkyl group (optionally having 1-5 substituents α₁ hereafter definedon the aryl moiety thereof), (v) C₁-C₆ alkylsulfonyl group, (vi) C₁-C₆halogenoalkylsulfonyl group, (vii) C₆-C₁₀ arylsulfonyl group (optionallyhaving 1-5 substituents α₁ hereafter defined) or (viii) C₇-C₁₆aralkylsulfonyl group (optionally having 1-5 substituents α₁ hereafterdefined on the aryl moiety thereof); A is a nitrogen atom or a═CH-group; B is an oxygen atom or a sulfur atom; W₁ is a C₁-C₈ alkylenegroup; W₂ is a single bond or a C₁-C₈ alkylene group; X is a (i)hydrogen atom, (ii) C₁-C₆ alkyl group, (iii) C₁-C₆ halogenoalkyl group,(iv) C₁-C₆ alkoxy group, (v) halogen atom, (vi) hydroxy group, (vii)cyano group, (viii) nitro group, (ix) C₃-C₁₀ cycloalkyl group, (x)C₆-C₁₀ aryl group (optionally having 1-5 substituents β hereafterdefined), (xi) C₇-C₁₆ aralkyl group (optionally having 1-5 substituentsβ hereafter defined on the aryl moiety thereof), (xii) C₁-C₇ aliphaticacyl group (xiii) C₄-C₁₁ cycloalkylcarbonyl group, (xiv) C₇-C₁₁arylcarbonyl group (optionally having 1-5 substituents β hereafterdefined), (xv) C₈-C₁₇ aralkylcarbonyl group (optionally having 1-5substituents β hereafter defined on the aryl moiety thereof), (xvi)monocyclic type heteroaromatic ring-carbonyl group (optionally having1-5 substituents β hereafter defined), (xvii) carbamoyl group, (xviii)C₇-C₁₁ arylaminocarbonyl group (optionally having 1-5 substituents βhereafter defined on the aryl moiety thereof) or (xix) amino group(optionally having 1 to 2 substituents β defined hereafter); Y is anoxygen atom or an S(O)p group (wherein p is an integer from 0 to 2); Z₁is a (i) hydrogen atom, (ii) C₁-C₆ alkyl group, (iii) C₁-C₆ alkoxygroup, (iv) C₁-C₆ alkylthio group, (v) halogen atom, (vi) C₆-C₁₀ arylgroup (optionally having 1-5 substituents α₁ hereafter defined), (vii)C₇-C₁₆ aralkyl group (optionally having 1-5 substituents αhereafterdefined on the aryl moiety thereof), (viii) C₆-C₁₀ aryloxy group(optionally having 1-5 substituents α₁ hereafter defined), (ix) C₇-C₁₆aralkyloxy group (optionally having 1-5 substituents α₁ hereafterdefined on the aryl moiety thereof), (x) C₃-C₁₀ cycloalkyloxy group,(xi) C₃-C₁₀ cycloalkylthio group, (xii) saturated heterocyclic ring-oxygroup (optionally having 1-5 substituents α₁ hereafter defined), (xiii)monocyclic type heteroaromatic ring-oxy group (optionally having 1-5substituents α₁ hereafter defined), (xiv) C₆-C₁₀ arylthio group(optionally having 1-5 substituents α₁ hereafter defined), (xv) C₇-C₁₆aralkylthio group (optionally having 1-5 substituents α₁ hereafterdefined on the aryl moiety thereof), (xvi) saturated heterocyclicring-thio group (optionally having 1-5 substituents α₁ hereafterdefined), (xvii) monocyclic type heteroaromatic ring-thio group(optionally having 1-5 substituents α₁ hereafter defined), (xviii) aminogroup (optionally having 1-2 substituents α₁ hereafter defined) or (xix)hydroxy group; said substituent α₁ is a (i) C₁-C₆ alkyl group, (ii)C₁-C₆ halogenoalkyl group, (iii) C₁-C₆ alkoxy group, (iv) halogen atom,(v) hydroxy group, (vi) cyano group, (vii) nitro group, (viii) C₃-C₁₀cycloalkyl group, (ix) C₆-C₁₀ aryl group (optionally having 1-5substituents β hereafter defined), (x) C₇-C₁₆ aralkyl group (optionallyhaving 1-5 substituents β hereafter defined on the aryl moiety thereof),(xi) C₁-C₇ aliphatic acyl group, (xii) C₄-C₁₁ cycloalkylcarbonyl group,(xiii) C₇-C₁₁ arylcarbonyl group (optionally having 1-5 substituents βhereafter defined), (xiv) C₈-C₁₇ aralkylcarbonyl group (optionallyhaving 1-5 substituents β hereafter defined on the aryl moiety thereof),(xv) monocyclic type heteroaromatic ring-carbonyl group (optionallyhaving 1-5 substituents β hereafter defined), (xvi) carbamoyl group,(xvii) C₇-C₁₁ arylaminocarbonyl group (optionally having 1-5substituents β hereafter defined on the aryl moiety thereof), (xviii)amino group (optionally having 1 to 2 substituents β defined hereafter)or (xix) carboxyl group; said substituent β is a (i) C₁-C₁₀ alkyl group,(ii) halogen atom, (iii) C₆-C₁₀ aryl group (optionally having 1-5substituents γ hereafter defined), (iv) C₇-C₁₆ aralkyl group (optionallyhaving 1-5 substituents γ hereafter defined on the aryl moiety thereof),(v) C₁-C₇ aliphatic acyl group, (vi) C₇-C₁₁ arylcarbonyl group(optionally having 1-5 substituents γ hereafter defined), (vii) C₈-C₁₇aralkylcarbonyl group (optionally having 1-5 substituents γ hereafterdefined on the aryl moiety thereof, (viii) C₄-C₁₁ cycloalkylcarbonylgroup, (ix) monocyclic type heteroaromatic ring-carbonyl group(optionally having 1-5 substituents γ hereafter defined), (x) carbamoylgroup or (xi) C₇-C₁₁ arylaminocarbonyl group (optionally having 1-5substituents γ hereafter defined on the aryl moiety thereof); and saidsubstituent γ is a C₁-C₆ alkyl group, a C₁-C₆ halogenoalkyl group, ahalogen atom or a hydroxy group; or a pharmacologically acceptable esterthereof, a pharmacologically acceptable amide thereof or apharmacologically acceptable salt thereof.
 74. A method according toclaim 73 wherein said active agent is an insulin resistance improvingagent.
 75. A method according to claim 73 wherein said active agent is ahypoglycemic agent.